Metabolism and the Circadian Clock Converge

Kristin Eckel-Mahan; Paolo Sassone-Corsi

doi:10.1152/physrev.00016.2012

. 2013 Jan;93(1):107–135. doi: 10.1152/physrev.00016.2012

Metabolism and the Circadian Clock Converge

Kristin Eckel-Mahan ¹, Paolo Sassone-Corsi ^1,^✉

PMCID: PMC3781773 PMID: 23303907

Abstract

Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis.

I. INTRODUCTION

Circadian rhythms control a wide variety of physiological events, including metabolism, in all organisms. Ingrained in our modern life-style is the flexibility to eat, sleep, socialize, and exercise around the clock, yet these allowances correlate with rising metabolic disorders and obesity. Increasingly evident is that metabolic homeostasis at the systems level relies on accurate and collaborative circadian timing within individual cells and tissues of the body. At the center of these rhythms resides the circadian clock machinery, an incredibly well-coordinated transcription-translation feedback system that incorporates a changing landscape of mRNA expression, protein stability, chromatin state, and metabolite production, utilization, and turnover to keep correct time. Recent findings show that regulation of metabolism by the circadian clock and its components is reciprocal. Specifically, components of the circadian clock sense alterations in the cell's metabolism. Understanding more fully the ties that exist between cellular metabolism and the circadian clock will provide not only needed insights about circadian physiology, but also novel approaches regarding both pharmacological and nonpharmacological treatment of metabolic disorders.

A. A Brief Overview of Circadian Physiology

The word circadian derives from the Latin circa (around) and dies (day). Oscillations of ∼24-h periodicity are referred to as circadian (FIGURE 1A). The molecular and physiological oscillations discussed here may vary in amplitude and even phase; however, in common is their ∼24-h periodicity (or tau, τ), which temporally follows the earth's rotation around its axis. Zeitgebers (the German word for “time givers”) are signals that help synchronize the body's circadian clock with the environment (TABLE 1). In mammals, light is one such zeitgeber and functions as such by activating a small region of the hypothalamus located just above the optic chiasm. Lesion studies identified this region, the suprachiasmatic nucleus (SCN), as being light responsive as lesions within this area abolished rhythmic circadian behavior in both locomotion and food consumption (224). The SCN is located in the anterior hypothalamus and is comprised of a meager 20,000 neurons, which receive photic information from the environment via neurons transcending from the retina via the retino-hypothalamic tract. The circadian system is organized hierarchically, meaning that while molecular oscillations occur in most cells and tissues of the body, the SCN functions as the master regulator, synchronizing the phase of other oscillating tissues (95, 204). Its superiority in this sense has been demonstrated in grafting experiments; SCN grafts from wild-type (WT) mice into a genetically arrhythmic mouse can restore normal circadian rhythmicity (227). Examples of SCN-directed circadian rhythms include feeding, the sleep-wake cycle, glucose metabolism, insulin secretion, and even learning and memory (95). Various techniques have been employed to measure and depict the properties of these rhythms including the simple actogram. Actograms graphically portray these rhythms, plotting activity in such a way that both the phase and period of the oscillation can be obtained. FIGURE 1B shows the actogram of a nocturnal animal's activity during the 24-h day, with dark shading representing their activity (in this case, wheel running) and blank areas reflecting the animal's rest or sleeping period.

Table 1.

Definitions for common circadian terminology and the core clock components of the mammalian circadian clock

Term	Acronym	Definition
Circadian		Refers to the ∼24-h nature of an event. Circadian is derived from the Latin roots “circa” (about) and “diem” (day).
Entrainment		Adaptation over time to an imposed cue such as light or food.
Zeitgeber	ZT	German word meaning “time giver”. A cue (such as light or food) that entrains the circadian clock. ZT refers to “zeitgeber time.”
Suprachiasmatic nucleus	SCN	A small region of the anterior hypothalamus consisting of bilateral nuclei that coordinately synchronize rhythmicity within other tissues.
Circadian clock-controlled gene	CCG	A gene expressed in a circadian-dependent manner, usually under the control of a promoter that contains an E-box, D-box, or RRE.
Brain and muscle Arnt-like protein-1	BMAL1	The mammalian bHLH-PAS transcription factor that dimerizes with CLOCK and NPAS2 to activate gene transcription.
Circadian locomotor output cycles kaput	CLOCK	The mammalian bHLH-PAS transcription factor that dimerizes with BMAL1 to activate promoters that contain E-boxes (CACGTG).
Cryptochrome proteins	CRY	Transcriptional repressors that dimerize with PER to inhibit CLOCK:BMAL1-mediated gene transcription. In plants and invertebrates, these function as light-responsive flavoproteins.
Neuronal PAS domain protein 2	NPAS2	A transcription factor similar to CLOCK and highly expressed in the forebrain. NPAS2 dimerizes with BMAL1 to activate gene transcription.
Period homolog proteins	PER	PAS domain containing proteins which dimerize with TIM (in Drosophila) or CRY (in mammals) to inhibit CLOCK:BMAL1-induced gene transcription. The Drosophila Period gene was the first circadian gene discovered.

Open in a new tab

Central to the molecular rhythmicity of SCN neurons as well as other oscillating cells are transcription factors that drive expression of their own negative regulators (204). This property of the clock results in a negative transcriptional and translational feedback loop that perpetuates oscillations in gene expression that occur every 24 h (FIGURE 1C). This program is highly conserved across species. FIGURE 1D demonstrates the corresponding positive- and negative-feedback proteins of this molecular system across several species. With the exception of the cyanobacteria circadian clock, the proteins in this table participate in the negative transcriptional translational feedback loop described. In mammals, two basic helix-loop-helix (bHLH) transcription factors, CLOCK and BMAL1 (also known as MOP3 or ARNTl), heterodimerize and subsequently bind to conserved E-box sequences in target gene promoters. In this way, they drive the rhythmic expression of mammalian Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) genes (FIGURE 2). PER and CRY proteins form a complex that translocates back to the nucleus to inhibit CLOCK:BMAL1-mediated gene expression. This deceivingly simple transcriptional feedback loop is regulated by highly complex mechanisms (such as posttranslational modification of circadian proteins and additional interlocking feedback loops of gene transcription) that mandate fine-tuning of the clock and yet provide for it plasticity by which it can adjust to changes in the environment (21, 38). While the clock genes are necessary for circadian physiology, a number of clock controlled genes (CCGs) also contribute. These are genes that are regulated by the circadian clock (and therefore oscillate with 24-h periodicity) but are not necessarily conserved across tissues.

Figure 2. — Additional inputs to the core circadian loop. The basic positive and negative transcriptional feedback loop of the circadian clock is elaborate, with external loops and posttranslational modifications, such as phosphorylation contributing to maintenance of the core oscillatory players. 5′ AMP-activated protein kinase (AMPK) and casein kinase I epsilon (CKIϵ) contribute to phosphorylation and degradation of the CRY and PER proteins, respectively, thus regulating the negative-feedback potential of these proteins on the CLOCK:BMAL1 complex. The transcription of *Bmal1* is negatively regulated by one of its own gene targets, *Rev-erb*α, the process of which controls the amount of BMAL1 protein available for CLOCK binding. Retinoic acid receptor-related orphan receptor alpha (RORα) exerts opposite effects to REV-ERBα on the *Bmal1* promoter.

While the view that this transcriptional and translational feedback loop is essential for timekeeping in cells has held preeminence, recent studies may revise the classical view of how rhythmicity is maintained within the cell. New data reveal that circadian rhythms can persist even in the absence of transcription. Specifically, the posttranslational modification of some proteins can occur in a transcription-independent manner (167, 168). This has been demonstrated by rhythmicity in the oxidation of peroxiredoxin proteins, for example, which is temperature compensated and entrained by zeitgebers, two fundamental qualities of circadian rhythms. While these transcription-independent oscillations occur, they do appear to exist in collaboration with the classical transcriptional loops described, as nucleated mouse embryonic fibroblasts from circadian arrhythmic animals show altered but present rhythmic peroxiredoxin oxidation. Thus there appears to be direct interaction between nuclear and cytoplasmic circadian rhythms when there is a nucleus present (168). Interestingly, the circadian oxidation-reduction cycles of peroxiredoxin are very highly conserved, even more so than the conservation that exists for the circadian clock components of FIGURE 1D (62). The idea that oscillations can persist in the absence of a nucleus is important because it means that there are likely numerous zeitgebers for the clock that are yet unidentified as such. In fact, the metabolome in its entirety may need to be addressed as possible zeitgebers and may feed into the clock system in specific ways, affecting phase, amplitude, or period of existing transcriptionally dependent oscillations. The concept of metabolites as critical modulators of the circadian clock will be further addressed in section IVB.

Circadian rhythmicity can be seen in many physiological processes. Examples include body temperature, activity, sleep, metabolism, heart rate, blood pressure, and hormone and neurotransmitter secretion (95). This being the case, it is perhaps not surprising that many cellular processes, including gene expression, oscillate within the cell. Approximately 10% of gene transcripts oscillate in the cell; however, a much larger percent of the proteome oscillates in either expression or activity (25, 57, 149, 180, 190). The large number of transcripts that oscillate in the cell depends in part on circadian changes in chromatin remodeling, perpetuated by rhythmic alterations in histone modifications such as phosphorylation or acetylation (161). Histone acetyltransferase and deacetylase activity at oscillating genes serves as a preamble for much of the rhythmic gene expression in vivo. Some of the chromatin modifying enzymes responsible for this activity may associate directly with circadian clock proteins (6, 162). CLOCK itself contains histone acetyltransferase activity which contributes to the rhythmic acetylation of K14 of histone H3 and K537 of its binding partner, BMAL1 (99). Recently, metabolites that fuel these rhythmic events have been observed to oscillate, sometimes producing rhythmic enzymatic activity even when the expression of a substrate's enzyme doesn't oscillate (163, 189). As more metabolites that contribute to clock maintenance are being identified, it is becoming evident that metabolism and circadian rhythmicity are intertwined molecularly and that one process cannot be adequately studied in isolation of the other. While much remains to be revealed in terms of their interactions, how oscillators in various compartments, from cells to tissues, interact to control metabolic physiology is beginning to be understood more fully.

B. Metabolic Homeostasis

Western (and what we generally consider as “westernized”) societies are experiencing a dramatic rise in metabolic disorders (14, 32, 61, 222). This rise is not limited to the adult population, as evidenced by an increase in overweight children and adolescents (222). The production of high-energy foods that are nutritionally wanting as well as the decrease in energy expenditure often associated with jobs that allow a sedentary life-style have certainly contributed to the occurrence of metabolic disorders. Genetics also contributes to alterations in metabolic function (88). In mammals, both environmentally induced circadian disruption as well as genetic aberrations in circadian clock machinery can lead to metabolic disorders (reviewed in Ref. 75). Why circadian disruption has this effect on metabolic homeostasis appears to be complex.

Energy balance is when energy (food) intake is equal to energy expenditure. Major sources of metabolic fuels include glucose, fatty acids, and ketone bodies. If not consumed, metabolic fuels are converted into metabolic stores including liver glycogen, muscle protein, and the triglycerides found in adipose tissue. Energy expenditure is a composite of three components: basal metabolic rate (energy to keep the nervous system working and the vital organs functioning properly), thermogenesis (the energy required for the absorption and storage of food), and physical activity (the most variable). Whether one is a 1.58 m, 86.2 kg individual or a 1.85 m, 72.6 kg individual, the body is remarkable in its ability to maintain energy equilibrium.

While genetics indubitably contributes to the body's ability to maintain energy balance (61, 88, 98), numerous studies have revealed that environmental cues including those affecting one's circadian rhythms also play essential roles in metabolic homeostasis (71, 97). With modern technology (which makes provisions such as exogenous lighting throughout earth's 24-h day), night shift and rotating shift work have become increasingly common. Such alterations beyond the conventional workday alter not only temporal aspects of work and social activities but also physiological and molecular rhythms in the body. Compelling evidence that circadian rhythm disruptions contribute to metabolic disorders has been observed in experiments centered on night shift and rotating shift workers. For example, an association between circadian disturbance and cardiovascular disease, increased body mass, and elevated plasma glucose and lipid levels has been observed in humans subjected to nighttime shift work (118, 120, 182, 234). Rodent studies also support this link as simply altering their normal light-dark cycle to one in which dim light replaces the normal dark period causes changes in metabolism that are observed on a physiological level (70). The integration of these processes at the cellular and systems level will be discussed further in later sections.

Rhythms in energy intake must coincide with endogenous fluctuations in gene expression for metabolic homeostasis at the cellular level to occur. At the cellular level, energy from our diet is used to generate macromolecules such as proteins, DNA, membrane components, and polysaccharides. As energy intake is a circadian activity, it drives fluctuations in the rate of these activities in different tissues. Furthermore, many of the oscillating gene transcripts in a given tissue are tissue specific or at least oscillate in a tissue-specific fashion (226). Tissues thereby meet their metabolic demands using regulatory molecules that are temporally or spatially distinct from other tissues. For example, many hormones that control food intake including insulin, glucagon, peptide YY, GLP-1, corticosterone, leptin, and ghrelin depend on energy intake or oscillate in a circadian manner, and are largely secreted in a tissue-specific fashion (reviewed in Ref. 75). The contrasting profile of nuclear receptor expression across different tissues also emphasizes the tissue-specific nature of metabolic gene expression. Numerous transcription factors, including metabolic nuclear receptors, display 24-h periodicity (250). These include receptors such as FXR, LXR, HNF-4α, PPARα, PPARγ, NUR77, and many others (www.nursa.org/10.1621/datasets.02001) that are more highly expressed in some metabolic tissues over others.

In summary, evidence that circadian and metabolic processes interact at the cellular levels is gaining strength and may help provide molecular explanations for the growing number of metabolic disorders associated with circadian disruption. Studies addressing this link at both the system and cellular levels are being performed and are illuminating some surprising effects of the clock on physiology.

II. SYSTEMS HOMEOSTASIS AND CIRCADIAN RHYTHMICITY OF PROCESSES INVOLVED IN ENERGY BALANCE

A. Feeding Is a Circadian Rhythm

The circadian regulation of energy intake is consistent across mammals. Mammals tend to consume the vast majority of food and water during their waking period. This occurs during the day for diurnal mammals and during the night for nocturnal animals and coincides with food-seeking activity. In mammals, feeding is under homeostatic control and involves humoral factors acting on hypothalamic neurons that ultimately control the urge to feed or not to feed. This is accomplished via endocrine molecules including leptin, ghrelin, and peptide YY acting on neurons within the hypothalamic arcuate nucleus (63). Neurons of the paraventricular nucleus both sense and integrate the orexigenic and anorexigenic signals that result from these hormones (reviewed in Ref. 181). These and other biological signals that control energy intake will be discussed in more detail in section IIIA2. Early lesion studies identified the SCN's contribution to circadian rhythmicity in eating and drinking as ablation of the SCN destroys rhythmicity in both eating and drinking (224). While it has been argued that early lesion studies may have involved tissue injury that extended beyond the SCN to other hypothalamic circuits, other models of circadian arrhythmicity also appear to be arrhythmic in energy intake when fed ad libitum (237). To some extent then, feeding is controlled directly or indirectly both by circadian and homeostatic processes.

Feeding that follows a typical pattern of daytime eating for diurnal organisms or nighttime eating for nocturnal organisms seems to be important for metabolic homeostasis. One recent study addressing the role of the circadian clock in metabolic function showed a somewhat surprising result: simply replacing the dark period of a rodent's circadian cycle with very dim light produced a pronounced increase in the rodents' body mass (70). Using a 16-h light/8-h dark cycle paradigm for control animals, the experimenters exposed some mice to a 16-h light/8-h dim light or a constitutively light paradigm. Interestingly, exposure to dim light at night caused increased energy intake during the daytime hours compared with animals in normal conditions, although total energy intake was unchanged between the two groups. An increase in body mass was detected in both experimental groups after only 1 wk of exposure to the new lighting paradigm, and this increase continued throughout the 8-wk program in the new lighting conditions. Epididymal fat pads were enlarged in experimental groups, indicating that changing the lighting conditions had an effect on white adipose deposition. As locomotion, corticosterone levels, and total 24-h energy intake were all unaltered in one or both of the experimental groups, only the increased percentage of energy intake that occurred during the day could account for the increased body mass observed in these rodents. When dim light-exposed animals were restricted to only nighttime feeding, the body mass alterations were prevented. While this study presents evidence that the normal circadian rhythmicity in food intake is important for metabolic homeostasis in rodents, the results support human studies in which night-eating syndrome (NES) is associated with obesity and circadian misalignment (170, 202, 231).

NES and sleep-related eating disorder (SRED) are two related eating disorders that include conscious or unconscious food consumption at night. They are typically associated with morning anorexia and evening hyperphagia as well as perpetual awakenings during the night that often involve eating (reviewed in Ref. 169). NES-inflicted individuals may wake from one to four times at night, and 74% of all awakenings are associated with food consumption (170). NES patients show a delayed melatonin rhythm and a phase advance of orexigenic ghrelin (which is released predominantly by the gastrointestinal tract) rhythms. The amplitude of ghrelin rhythms is also decreased in NES individuals (81). While plasma glucose levels are antiphase to control human subjects, insulin levels are phase delayed and are also considerably reduced in amplitude in NES-afflicted subjects. As NES reflects a phase delay in the acquisition of food, potential circadian mechanisms underlying the disease are under consideration. Sertaline, a selective serotonin reuptake inhibitor (SSRI), has been shown to reduce the amount of nighttime calories consumed in NES-afflicted individuals and may do so by altering rhythms at the level of the SCN (171). It is still unclear whether NES individuals represent a situation in which uncoupling of peripheral oscillators with the central clock occurs or whether individual peripheral oscillators are functioning out of phase with each other independent of central clock coherence. NES-afflicted individuals, however, support other evidence that implicates clock disturbances with metabolic disorder.

B. Food as a Zeitgeber, a Metabolic Circadian Cue

While originally thought to be limited to the brain, the occurrence of circadian rhythms has been noted throughout tissues of the body. In fact, most tissues studied to date show robust oscillations in gene expression (254). There are few known zeitgebers, however, that can entrain the circadian clock in vivo. Those identified include light and, more recently, food. As a light pulse during the subjective night can phase advance or delay the SCN circadian clock, food can function as a potent zeitgeber for peripheral tissues, underscoring the important relationship between circadian and metabolic processes. The circadian rhythm of the SCN, which responds robustly to light, is largely unaffected by changes in feeding patterns, while oscillations within some peripheral tissues, such as the liver, appear to be dependent on communication with a rhythmic brain but principally on the feeding cycle. For diurnal animals, like humans, feeding occurs during the day, whereas for nocturnal organisms, food intake takes place predominantly at night, when they are awake and active. Feeding and circadian rhythms in gene expression are so tightly linked that, when food is restricted to a precise time of the day, the expression of a large number of hepatic genes is altered, with a new rhythm that follows that of the feeding cycle (37, 225). One study demonstrating the zeitgeber property of food involved mice that were restricted to 4 h of feeding during their rest period. As early as 2 days after restricted feeding, the liver showed a 10-h phase change in circadian rhythmicity. Analysis of several tissues from animals that were fasted following a week of restricted feeding showed that not only the liver but also the lung had been entraining to the new restricted feeding schedule. Conversely, in a liver which lacks normal circadian rhythmicity, the majority of hepatic gene expression rhythms can be restored by exposure to a temporally restricted feeding schedule (237). Technically, food can entrain both the periphery and the brain, as a free-running animal that is exposed to a restricted feeding schedule can show signs of SCN entrainment (as measured by wheel running, for example) that may be caused directly or indirectly by food and the anticipatory activity involved in its administration (reviewed in Ref. 156). The restriction of feeding to a few hours during an animal's normal resting period results in food anticipatory activity (FAA), in which locomotion patterns deviate from normal circadian cycles (64). Such enhanced activity during the rest period serves as a preamble to the feeding event, indicative of the animal's anticipation of food consumption. While still under investigation, a functional clock in the dorsomedial hypothalamus (DMH) has been implicated in FAA (77). Bmal1 knockout animals and Clock mutant animals, both of which show complete arrhythmia, however, can still show FAA under some experimental conditions (183, 185), so it is unclear what role the circadian clock might play in the central nervous system for FAA to occur. Entrainment to food can also occur in rodents with SCN lesions (127, 223), indicating that the neuronal locations governing FAA are at least partially distinct from those which participate in light entrainment. Interestingly, ghrelin seems to stimulate the appetitive and consummatory aspects of food intake during feeding restriction, and ghrelin receptor knockout animals show a reduction in FAA (141). While the arcuate nucleus is one of several ghrelin-expressing regions of the brain that could account for the change in FAA in ghrelin receptor knockout animals, other molecules in satiety centers also contribute to this process. The melanocortin 3 receptor, for example, is highly expressed in food-responsive regions of the hypothalamus and responds to anorexigenic hormones so as to lower energy intake and increase energy expenditure. Melanocortin 3-receptor knockout mice have increased adiposity (27) and, interestingly, melanocortin 3 knockout mice are immune to FAA (16, 228). Knockout of the melanocortin 3 receptor in mice demonstrates its importance for the circadian timing of food consumption but also for entrainment of anticipatory behavior to feeding time.

In summary, feeding is a circadian event. However, it serves not only as an output of the clock but also as a clock input mechanism, particularly for peripheral tissues. Because peripheral tissues communicate back to the brain via ghrelin, leptin, glucose, insulin, etc., circadian feeding contributes to an intertwining of the clock and metabolism that appears to be crucial for metabolic homeostasis.

C. Circadian Rhythmicity of Energy Expenditure

Energy expenditure involves the maintenance of one's basal metabolic rate, the maintenance of resting metabolic rate, physical exercise, and the maintenance of core body temperature. The vast majority of energy expended in an organism goes towards maintaining one's basal metabolic rate, and this directly affects body temperature. Core body temperature oscillates in a circadian fashion with a peak that occurs during the early evening in humans and a trough during the early morning hours. Human subjects isolated in free running conditions (i.e., in the absence of zeitgebers such as light) still show oscillations in core body temperature and sleep/wake cycles (259). Heart rate follows the temporal profile of body temperature, with beats per minute reaching a nadir around ZT3 in human subjects. Interestingly, thermoregulatory changes appear to be tied into the sleep/wake cycle and are important for the circadian modulation of sleepiness and propensity to sleep (126). A fraction of spent energy is in the form of physical exercise, and this type of energy expenditure is highly variable across the population. Some human performance measures including muscle strength, anaerobic power output, and joint-flexibility follow the circadian pattern of core body temperature (reviewed in Ref. 192). Therefore, studies have addressed whether sports performance, for example, or exercise is optimal at specific zeitgeber times. An interesting concept is that rigorous exercise might be part of the reciprocal interplay between the circadian clock and metabolism. Recent attention has been paid to the idea that exercise might actually function as a zeitgeber for the body. This promises to be an intriguing area for future study.

D. Malfunctioning Clocks and Metabolic Disease

Recent data from night shift workers and individuals with sleep disorders provide evidence that metabolism and circadian rhythms are tightly linked in vivo. The implications of this are probably widespread. With the use of the definition that shift work is that which occurs during nontraditional working hours (usually from 10 p.m. to 6 a.m.), almost 20% of workers in industrialized nations are considered to be shift workers (5). Experiments focused on the effects of shift work indicate that shift workers show an increased prevalence of obesity and that they gain more weight than workers engaged in a conventional workday. In one study, shift workers showed a higher body mass index (BMI) compared with normal shift workers, an increase that did not correlate with age or length of time at the nonconventional shift work (44). Other studies generally support this trend, although in some cases a correlation has been found between length of time at the shift work and BMI (reviewed in Ref. 58). One study tracked male, Japanese workers for up to 27 years to assess whether the night shift population within the manufacturing sector showed an increased risk of obesity relative to their male counterparts who worked only the day shift (128). An increase in obesity was observed in night shift workers, and after 10 years of follow up, a pronounced risk was observed. A similar study designed to assess the effects of alternating shift work on body weight showed that job schedule was associated with BMI but that drinking habits and age were negatively correlated with increases in BMI (229). Cross-sectional data accumulated from the Västerbotten intervention program supports these results. Data collected from shift workers participating in health surveys at ages 30, 40, 50, and 60 years of age indicate that obesity is more prevalent in female shift workers of all ages. Men in some age groups also showed a propensity for obesity (117). Furthermore, high-density lipoproteins were generally decreased in younger shift workers and after adjusting for age and socioeconomic factors, a high level of circulating triglycerides was a risk factor in both sexes. These studies clearly demonstrate a correlation between night shift work and metabolic disturbance, but may even underestimate the damaging effects of circadian dysrhythmia as workers having difficulty adapting to night shifts are often moved back to daytime shifts and are therefore removed from analysis such as these (128).

Unarguably, shift workers have a hard time adjusting completely to a new phase of zeitgebers (198). A new phase of schedule means that the phase of endogenous rhythms will need time to adjust. For example, food consumption generally takes place during the waking nighttime hours in night shift workers, often resulting in an additional meal consumed during the 24-h day. This requires peripheral clocks to adapt and alter the phase of humoral rhythms such as those of ghrelin. The brain must also adapt to a new sleeping schedule during the day, a task that is arduous as some shift workers report (53). Many shift workers complain of fatigue, jetlag type symptoms, gut disturbances, among other circadian-related maladies, implying that desynchrony might last a very long time, because the internal clocks of the body are not cohesive with the new environment (53). Besides the obvious physical manifestations of fatigue, pain, and discomfort, there appear to be further and yet unexplored ramifications of an internal clock that is out of phase with its environment.

One concern with this internal and external desynchrony is that the levels of coronary artery disease associated with shift workers are rising. One study looking at United States female nurses who worked rotating night shifts (defined as equal to or greater than three nights per month as well as additional day and evening shifts) reveals that women who worked 6 years or more of shift work had an increased risk of coronary heart disease after correcting for smoking among other risk factors (120). A recent summary of 17 prior studies focused on shift work and cardiovascular diseases (reviewed in Ref. 122) reveals that shift workers had a 40% increased risk of cardiovascular disease relative to exclusively daytime workers. It is well known that several heart-related conditions manifest more frequently at particular times of the day. Ventricular tachycardia, cardiac arrest, acute mycoradial infarctions, and myocardial ischemia have all been reported to manifest in a circadian fashion (reviewed in Ref. 52).

To better understand the mechanisms behind internal synchronization, experiments with rodents have been designed to mimic human night shift work. One such study used a wheel-running task imposed on nocturnal rats either during their normal sleep phase or during their normal wake phase. Interestingly, plasma glucose rhythmicity was lost entirely in rodents that “worked” during their sleep phase and serum triglyceride (TAG) levels were reversed from those of control animals, with peaks occurring during the sleep phase (201). To address whether internal desynchrony was present, PER1 and PER2 protein expression was analyzed in the SCN in control and working groups where it was found both in phase and of comparable amplitude in the SCN of sleep phase-working animals relative to controls. Corticosterone levels were also invariant, other than an initial rise when animals began their work phase, regardless of zeitgeber time. After 3–4 wk of sleep-phase work, rats subjected to work during the sleep phase gained more weight than their counterparts that worked during the waking phase, supporting human studies showing a similar profile of adiposity and weight gain in shift workers. It is likely that such desynchrony also exists in humans. If pharmacological treatments could be devised to help assist in internal and external synchronization, perhaps some of the negative effects associated with shift work might be avoided.

Perhaps a more common form of circadian desynchrony comes in the form of social jetlag, when individuals are not sleeping within the normal circadian sleep window due to time schedules imposed by work or shool, social events, etc. Recent studies addressing this common problem show that even social jetlag is associated with obesity (195). Importantly, sleep timing appears to be as important a regulator of body mass index as sleep duration.

III. CIRCADIAN RHYTHMS IN METABOLIC TISSUES

A. How the Brain Talks to the Periphery and Vice Versa

As the synchronizer of rhythms throughout the body, the efferents of the SCN play a paramount role in the circulation of humoral factors that target peripheral tissues. Many SCN efferents are contained within regions of the hypothalamus itself (FIGURE 3). The core region of the SCN, which assimilates photic and nonphotic input from the retinohypothalamic tract and the raphe, respectively, appears to project predominantly to the lateral subparaventricular zone (207). Conversely, the shell of the SCN, which receives input from the limbic forebrain and other hypothalamic loci, projects predominantly to the medial subparaventricular zone and the dorsomedial hypothalamus (139). In a circuit that includes the paraventricular nucleus and the intermediolateral nucleus in the thoracic spinal cord, the SCN communicates with the pineal gland, using sympathetic neurons of the superior cervical ganglion, thus regulating the rhythmic secretion of melatonin. Melatonin shows peak expression during the dark phase in both nocturnal and diurnal animals (157) and directly feeds back into the clock by targeting receptors in the SCN. The effects of melatonin on physiology are diverse. For example, melatonin appears to have a strong effect on blood pressure, and its receptors are found throughout the blood vessels of many arterial beds (reviewed in Ref. 193). Oscillating melatonin levels probably contribute to the normal circadian variations in human blood pressure. As ambulatory heart rate is a circadian controlled function, melatonin has been used to reduce blood pressure in patients with hypertension (203). The decrease in human blood pressures in both normo- and hypertensive patients after melatonin administration is consistent with rodent studies where melatonin therapy is an effective treatment for rats with spontaneously high blood pressure (230). Melatonin probably provides this effect, in part, because it relaxes the smooth muscle wall.

Figure 3. — Main outputs of the SCN as revealed by anterograde labeling experiments. SCN neurons project to numerous other regions of the central nervous system, the large majority of which are hypothalamic. SCN efferents include the paraventricular thalamic nucleus, the subparaventricular zone, the hypothalamic paraventricular and dorsomedial nuclei, the tuberomammillary nucleus, and the medial preoptic area. The SCN communicates to the periphery in part via humoral signals released by other tissues of the central nervous system and via the sympathetic and parasympathetic nervous system. Some SCN-targeted peripheral tissues include white and brown adipose tissue, the gallbladder, the thyroid gland, the kidney, the spleen, the adrenal gland, the thyroid, the liver, the pancreas, and the submandibular gland (1, 13, 207, 239).

The SCN uses the autonomic nervous system, including both the parasympathetic and sympathetic systems to regulate the periphery. Glucocorticoids, which are released in a cyclical fashion from the adrenal cortex, are controlled by the circadian clock. Glucocorticoids oscillate in both an ultradian and circadian fashion, with circadian peaks occurring during the early morning for diurnal animals and early evening for nocturnal animals (reviewed in Ref. 46). Adrenocorticotropic hormone (ACTH), which is released by the corticotrope cells of the pituitary, shows a similar profile and stimulates the release of the steroid hormone corticosterone from the adrenal cortex. Light inhibits the release of corticosterone, and in SCN-lesioned animals, light does not produce the normally observed depression of corticosterone release. Corticosterone production is linked to the environment indirectly and probably depends on SCN relays to the paraventricular nucleus (22). The circadian regulation of corticosterone is important for physiology, as corticosterone serves not only as a precursor for aldosterone, but it also functions in rodents and other mammals as a glucocorticoid, playing central roles in liver metabolic function. Interestingly, in SCN-lesioned animals, where at least some of rhythmic liver gene expression is lost, rhythmicity can be restored by the administration of glucocorticoid receptor activation, suggesting the critical nature of SCN-regulated glucocorticoid release in the regulation of peripheral oscillations (191).

Other humoral factors such as vasopressin and acetylcholine are also used to communicate to the periphery by the clock in the brain. Perhaps one of the best known oscillating humoral factors is arginine vasopressin (AVP). Vasopressin is released into the bloodstream by the pituitary, and it affects the periphery by regulating blood pressure and by decreasing water elimination from the kidney during periods of dehydration. Its circadian release by the pituitary into the cerebrospinal fluid is SCN-dependent (208), but it is also released by the SCN itself where it plays an important role in neuronal synchronization within the structure (8, 111). Acetylcholine is another oscillating neurotransmitter that affects the periphery by inducing skeletal muscle contraction while inhibiting cardiac muscle contraction. In vivo microdialysis techniques demonstrate that there is a circadian release of acetylcholine (113). Acetylcholine serves as the primary neurotransmitter for preganglionic sympathetic neurons, ultimately controlling processes as disparate as heart contraction and gluconeogenesis in the liver. Acetylcholine contributes to timekeeping in the central pacemaker as well and can phase shift SCN rhythms via SCN muscarinic acetylcholine receptors (145). Finally, as demonstrated in viral tracking experiments, the SCN uses the sympathetic nervous system to communicate with a number of peripheral tissues. Peripheral injections of pseudorabies virus (useful for the analysis of identifying transynaptic circuits) in brown adipose and white adipose tissues have revealed that the SCN projects via the sympathetic nervous system to these tissues among many others (reviewed in Ref. 13).

The role of communication provided by the periphery to the brain in controlling energy homeostasis is paramount because the periphery releases a large number of factors such as adipokines and hormones that communicate back to the brain. Such signals provide information to the central nervous system that the peripheral demands have been met or need to be met. Leptin and ghrelin are two such hormones. Ghrelin, which is predominantly secreted by a small fraction of cells in the stomach, signals to the brain that the body needs to be fed. It acts on receptors in the brain in a manner that opposes the actions of leptin and stimulates food consumption by driving feelings of appetite and hunger. Ghrelin levels plummet after a meal, whereas in anticipation of a meal, levels rise again. This oscillatory activity produces changes in ghrelin levels of approximately sixfold in the blood (147). Ghrelin is modified by an eight-carbon fatty acid residue that is central to ghrelin's effects in the brain, and the unmodified and octanoylated forms of ghrelin circulate in the blood (110). Ghrelin is essential for growth hormone release and is highly conserved across mammals. This is accomplished via hypothalamic arcuate neurons that release growth hormone releasing factor (GHRH), which then activates the release of growth hormone from the pituitary. Ghrelin receptors are also present in the pituitary and can contribute to the release of growth hormone during times of starvation (82). Also released by the periphery, glucose and insulin play seminal roles in the central nervous system to regulate energy intake and metabolism. Recent work on insulin signaling in the brain highlights neurons of the ventromedial hypothalamus as insulin-responsive regulators of diet-induced obesity. While the ablation of the insulin receptor in steroidogenic factor 1 (SF-1) cells of the ventromedial hypothalamus (VMH) has no effect on animals fed a normal diet, when challenged with a high-fat diet, animals devoid of the insulin receptor in this region are partially protected from obesity and show enhanced peripheral glucose metabolism compared with WT control mice. Insulin appears to induce hyperpolarization of VMH SF-1 neurons, which reduces their glutamatergic output to proopiomelanocortin (POMC)-expressing neurons of the arcuate nucleus, thereby inhibiting anorexigenic output. When insulin signaling is impaired in this region, anorexigenic output is enhanced, leading to protection against adiposity.

B. Circadian Rhythmicity Within Metabolic Tissues

While once thought to be restricted to the SCN, it is now clear that peripheral tissues host clocks and engage in precise and yet entrainable timekeeping necessary for circadian physiology. As measured in rodents using luciferase activity driven by the Per2 promoter, most tissues show circadian rhythmicity that dampens over time in the absence of the SCN (254). Interestingly, rhythmicity in gene expression within tissues is generally unique, generating phase and period-specific oscillations over the circadian cycle. The brain also shows tissue-specific oscillations in gene expression, which can be independent of SCN rhythmicity (83, 84). While some rhythmic genes are tissue specific, others are shared across many tissues. Some of the clock genes (Per2, for example) show rhythmicity across many different tissues as do Bmal1, Rev-erbα, and the Cry genes (249). Some unlikely molecular candidates linking the circadian clock to specific metabolic tissues are being revealed, however, and are illuminating new ways by which circadian physiology may be controlled in tissue-specific ways.

The sirtuin family of proteins is becoming recognized for its peripheral and central role in both circadian rhythmicity and metabolism. The sirtuin family is composed of seven family members, some of which are mitochondrial (SIRT3, SIRT4, and SIRT5) and others that are principally cytoplasmic (SIRT2) nuclear (SIRT1, SIRT6, and SIRT7) or expressed in more than one compartment within the cell (91). Sir2 (silent information regulator 2, the homolog of the mammalian SIRT1) is an NAD⁺-dependent histone deacetylase, perhaps best known initially for its role in longevity (135, 144), although it is not clear that it contributes to a longer life span in all species (24). Consequently, the mammalian ortholog of Sir2, SIRT1, has emerged as a central component linking the circadian clock to metabolism. SIRT1 is a class III histone deacetylase and differs from the class I and II deacetylases in that it requires NAD⁺ as a cofactor for its enzymatic activity. SIRT1 breaks down NAD⁺ during the process of lysine deacetylation producing O-acetyl-ADP-ribose. During fasting, levels of NAD⁺ are high, and the activity of SIRT1 is elevated (194). However, when energy is in excess, NAD⁺ is depleted because the rampant flux through the glycolytic cycle promotes the conversion of NAD⁺ to NADH. Recent studies demonstrate that SIRT1 directly interacts with circadian clock machinery and that its enzymatic activity contributes to robust oscillations of rhythmic genes in vivo (17, 162). Some studies show that the enzyme is constitutively expressed, while others demonstrate rhythmicity in expression (17, 162). What is clear, however, is that its enzymatic rhythmicity is due in part to an oscillation in the levels of the enzyme's cofactor NAD⁺. In search of the source of SIRT1's oscillating activity, it was discovered that CLOCK:BMAL1 directly regulate the nicotinamide phosphoribosyltransferase (Nampt) gene promoter, the activation of which provides its expression (163, 189). This activation is remarkable in that NAMPT provides the rate-limiting step in the NAD⁺ salvage pathway. In this way, the classical circadian transcriptional loop is linked to an enzymatic feedback loop in which SIRT1's own activator is produced in a circadian manner by the circadian clock machinery (FIGURE 4) (59). While initially identified as a histone deacetylase, SIRT1 also targets non-histone proteins. In the fasted sate, SIRT1 activity affects the activity of numerous target proteins including many involved directly or indirectly in metabolic homeostasis. These target proteins include PGC-1α, FOXO, IRS1/2, LXR, HNF-4α, FXR, RAR, TORC2, BMAL1, eNOS, LKB1, AMPK, and SREBP (reviewed in Refs. 68, 142). SIRT1-mediated deacetylation of PGC-1α activates the protein, and therefore promotes gluconeogenic gene transcription and the inhibition of glycolytic gene transcription in the liver (194). SIRT3 appears to be the major mitochondrial protein deacetylase where it deacetylates targets such as acetyl-CoA synthetase, lecithin-cholesterol aceyltransferase, and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and thereby controls the levels of ketone body production (100, 209, 213). While little is known about the circadian regulation of SIRT3, as a consumer of NAD⁺, it is likely that SIRT3 activity, like SIRT1, is activated in a circadian manner. The full extent to which the sirtuin family affects tissue-specific oscillations remains to be seen; however, the ubiquitous expression of the sirtuin proteins across metabolic tissues indicates that their roles in the circadian clock are likely to be important for metabolic homeostasis.

Figure 4. — The sirtuins link circadian rhythmicity to metabolism. The SIRT1:CLOCK:BMAL1 complex drives expression of *Nampt*, the rate-limiting enzyme in the salvage pathway for SIRT1's own cofactor, NAD⁺. The two loops depicted in the figure demonstrate the mechanisms of both the transcriptional feedback circuit as well as the enzymatic feedback circuit.

Oscillations within the family of peroxisome proliferator-activated receptor (PPAR) genes have been shown to be prominent in several tissues, including the liver, muscle, brown adipose tissue and white adipose tissue (250). As regulators of lipid storage and lipogenesis, hepatic fatty acid oxidation, and ketogenesis, this family of proteins provides an important link between peripheral rhythmicity in metabolic tissues. A key regulator of gluconeogenesis and glycolysis, the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) provides an additional contribution to clock ticking in metabolically active tissues via its regulatory role in Bmal1 gene transcription. Specifically, PGC-1α acts in concert with RORα to activate Bmal1 gene transcription and, in so doing, links metabolism to the circadian clock (146). In Pgc-1α null mice, circadian clock gene expression is altered, and the circadian oscillation amplitudes of oxygen consumption are considerably dampened while total levels of V̇o₂ are elevated across both day and night (146).

1. Circadian rhythmicity in the brain

A) CIRCADIAN OSCILLATIONS IN NEURONS OF THE CENTRAL PACEMAKER.

The mammalian SCN responds to light via neurons that extend from the retina of the eye and through the retinohypothalamic tract. The light responsiveness of these neurons provides synchronization of the organism to the surrounding light-dark cycles. When an organism is put in an environment that deviates from the 24-h cycle, the endogenous circadian clock must reset during a process known as entrainment. The entrainment process takes time (days to weeks) and temporarily renders a desynchronization between the brain and peripheral clocks. For example, the disruption of the endogenous clock during travel across time zones gives one the experience of jetlag, as homeostatic and circadian cues are temporarily out of sync. The endogenous circadian clock must entrain to the new light/dark conditions, a process that relies on distinct signaling transduction pathways that lie upstream of the transcriptional translational loops of the clock machinery already described.

While the clock machinery is required to maintain circadian oscillations in the SCN (i.e., Bmal1 knockout animals and Clock mutant mice have altered circadian rhythms in SCN tissue), much of the complexity that lies upstream of these transcriptional activators has been revealed. The SCN receives nonphotic information from the geniculohypothalamic tract, the dorsal raphe nucleus, and the median raphe nucleus (reviewed in Ref. 45). While some redundancy exists, generally the photic input relayed via the retinohypothalamic tract is independent of rods and cones but relies on photosensitive retinal ganglion cells (18). Photic and nonphotic inputs are integrated in the SCN by various signal transduction pathways. Neurons of the SCN respond to pituitary adenylyl cyclase activating peptide (PACAP) during the day, which produces neuronal depolarization (93). At night, neurons of the SCN respond to acetylcholine as well as other cGMP-activating analogs (79). While nonphotic SCN resetting can occur via serotonergic innervation of the SCN (217), light exposure during the night can also reset the SCN clock by triggering the release of glutamate from retinal ganglion cells and a resulting activation of NMDA receptors on SCN neurons. The subsequent depolarization of SCN neurons leads to activation of calcium-sensitive adenylyl cyclases in the SCN and the production of cAMP. cAMP activates proteins such as the guanine nucleotide exchange factors (EPAC proteins) as well the mitogen-activated protein kinase (MAPK) signaling cascade, which in neurons couples depolarization to transcription via activation of cAMP response element binding protein (CREB). Indeed, organisms exposed to a light pulse at night show a rapid and robust MAPK phosphorylation in the SCN as well as phosphorylation of CREB and activation of CRE-mediated gene transcription (172, 173). There is direct evidence that cAMP oscillations are required for normal circadian rhythmicity (166). Noncompetitive inhibition of cAMP-producing adenylyl cyclase enzymes in the SCN severely prolongs locomoter periods in rodents, an event which is abrogated by mutations in the central clock machinery. Furthermore, adenylyl cyclase activators can reset the clock, producing robust changes in the amplitude of gene expression, dependent on the circadian time at which activators are administered.

The neuronal signaling that occurs in response to light would be useless without the ability of SCN neurons to properly synchronize with each other. SCN neurons in culture show circadian rhythmicity in firing, although synapses between the neurons are not necessary or sufficient for this rhythmicity (241). In fact, cultured SCN neurons that oscillate in firing rate can vary drastically in phase from neighboring cells. Phase coherence in vivo is thought to be mediated at least in part via the secretion of vasointestinal polypetide (VIP), which is released from <25% of SCN neurons (8). VIP appears to be dually important for rhythmicity in some of the SCN pacemaker cells and synchrony in others. Interestingly, one of the receptors for VIP, the G protein-coupled VIPR2 (or VPAC2), not only contributes to maintenance of normal circadian rhythmicity but also to metabolic homeostasis. Loss of this receptor interferes with circadian rhythmicity in rodents (94, 102, 212) and reduces metabolic output during the active cycle (15). Vipr2 knockout animals show a reduction in both oxygen consumption and carbon dioxide output during the nighttime waking hours, and much of their food consumption is advanced into the resting period. Additional studies also support the link between VIP signaling and metabolic homeostasis. For example, VIP knockout mice have elevated plasma glucose, insulin, and leptin levels, probably due to the expression of VIP receptors on taste cells which in the absence of VIP affects the tongue's role as a sensory gate for energy intake (153).

The SCN modulates the circadian release of multiple neurotransmitters and hormones but responds to many of them in turn. For example, the SCN is required for rhythmic melatonin release from the pineal gland, but the SCN also responds to melatonin, and can be reset by the activation of its own melatonin receptors (178). Similar regulation by and feedback to the SCN is observed with other hormones and neurotransmitters as well. While peripheral tissues respond acutely to glucose demands, the brain anticipates glucose demands. It accomplishes this, in part, by communicating with the periphery to release glucose and insulin in a circadian manner. In humans, insulin release is highest during the early morning hours, when the body anticipates upcoming glucose metabolism (19, 131, 232). There is evidence that the SCN participates in maintaining this balance as lesions of the SCN eliminate plasma glucose and insulin rhythmicity (159, 160). These oscillations appear to be independent of a loss of rhythmicity in food intake (131). Circadian oscillations in glucose and insulin production are also controlled by inhibitory and excitatory inputs into the preautonomic neurons of the paraventricular nucleus (PVN) via the SCN. Stimulation of preautonomic neurons of the PVN via the GABAergic antagonist bicuculline produces hyperglycermia but only during the light period, while exciting neurons of the PVN via the glutamatergic agonist NMDA does not show this time-of-day effect (112). The SCN appears to use rhythmic GABAergic projections to control the activity level of sympathetic preautonomic neurons of the PVN as SCN-lesioned animals show no circadian variation in hyperglycemia after GABAergic antagonism.

B) CIRCADIAN OSCILLATIONS IN FOOD ENTRAINABLE ENSEMBLES OF THE BRAIN.

As the hypothalamus plays a central role in feeding, how the circadian clock affects hypothalamic function has been a recent focus of interest. Lesion experiments that predate the 1950s reveal that while disruption of the medial hypothalamus causes hyperphagia and obesity, lesions of the lateral hypothalamus lead to a cessation of food consumption (reviewed in Ref. 47). The arcuate nucleus of the hypothalamus plays a unique role in metabolic homeostasis. Within this structure are two neuronal populations that contribute profoundly to energy homeostasis: one population consists of orexigenic neurons [expressing the neuropeptide Y (NPY) and agouti-related peptide (AgRP)] and another population consists of anorexigenic neurons [which express proopiomelanocortin-derived peptides including the α-melanocyte stimulating hormone (MSH) and cocaine- and amphetamine-regulated transcript (CART) proteins]. Both of these neuronal populations project to the PVN, where AgRP antagonizes melanocortin receptors and α-MSH functions as an agonist at melanocortin receptors (66, 150). Thus injection of NPY into the paraventricular hypothalamus causes an increase in food intake (220). Interestingly, NPY has been shown to oscillate in a circadian fashion, an oscillation which is controlled in part by both serotonin and GABA and is abolished by feeding restriction (80, 246). Serotonin enhances NPY release while GABA (which also oscillates in a circadian fashion) inhibits NPY release in the SCN. The adenylate cyclase-coupled melanocortin receptors respond to these peptides, and knockouts of these receptors have demonstrated their importance in energy homeostasis. Melanocortin 3 (MCR-3) and melanocortin 4 (MCR-4) receptor knockout animals are both obese, with MCR-3 rodents being obese without hyperphagia. MCR-4 mutations are known to cause obesity in both humans and rodents (67, 105). The melanocortin-secreting cells of the arcuate nucleus are highly responsive to leptin (184). The precise mechanisms underlying leptin's effects on body weight are still unclear, but leptin receptors in GABA-secreting neurons appear to contribute greatly to body weight regulation. Specifically, the elimination of leptin receptors from all GABA-secreting neurons but not gluatamatergic neurons promotes dramatic increases in food intake and body fat mass (238).

Ghrelin produces its orexigenic effects by triggering the activation of the growth hormone secretagogue receptor (GHSR). GHSR was first identified as ghrelin-responsive in the pituitary, where its activation triggers the release of growth hormone (123). Ghrelin's receptors are also abundant in the hypothalamus, and the GHSR-mediated activation of AMPK in hypothalamic neurons culminates in increased mitochondrial fatty acid oxidation within NPY-expressing cells and GABA-mediated inhibition of NPY/AgRP neighbor POMC neurons (124). As a result, feeding is increased in response to ghrelin release from the stomach. This chain of events bears circadian influence at multiple steps. First of all, ghrelin oscillates in a circadian fashion (141). Second, the increased fatty acid oxidation depends on cofactors that have been shown to oscillate in other tissues, such as NAD⁺ (163, 189). As the molecular machinery required for the feedback loops depicted in FIGURE 4 are intact in hypothalamic circuits, it is quite possible that a similar circadian profile can be expected for NAD⁺-regulated processes in melanocortin neurons.

2. The hepatic circadian clock

Due to the relative importance of the liver in glucose and lipid homeostasis, its participation in the circadian clock is of central importance to metabolic physiology. In fact, the liver has been a central target in the study of circadian rhythmicity as it displays robust oscillations in circadian output genes as well as in genes specific to the hepatic system (2). Hepatic rhythmicity depends in part on the rhythmic intake of food which is preserved in constant dark conditions. Interestingly, even under the influence of a functional central clock, the vast majority (over 80%) of hepatic genes are rhythmic in response to food intake (237). Conversely, in mice devoid of circadian rhythmicity, such as is the case in Cry1^−/−/Cry2^−/− double knockout mice, restricted feeding can restore rhythmicity to many genes in the liver that are otherwise arrhythmic in expression. While SCN lesions generally abolish circadian rhythmicity in the liver, strong transcriptional activators, such as the glucocorticoid receptor, can confer rhythmicity to gene expression made arrhythmic by SCN lesions (191). In spite of the influence of food intake on the hepatic clock, the core clock proteins still hold a prominent role in maintaining the hepatic clock. Clock mutations or deletions such as the Clock^Δ19 mutation and the Clock exon 5 deletion severely affect the hepatic circadian system as demonstrated in numerous rodent studies (41, 42, 154). Bmal1 knockout mice are arrhythmic in the brain and the liver as are the Clock^Δ19 mice (154, 236). Interestingly, Clock knockout mice show some arrhythmicity in the liver while remaining rhythmic in the brain, underscoring the tissue-specific role of CLOCK protein in the liver. While NPAS2 protein can compensate for loss of Clock in the brain, it does not compensate for loss of CLOCK function in the liver (42, 43).

These results demonstrate rhythmicity of gene expression in the liver, although not to be ignored is the fact that as much as 20% of liver-soluble proteins are subject to circadian regulation (190). In fact, for almost 50% of rhythmic proteins identified in the liver, no oscillation in the corresponding mRNA levels can be observed, underscoring the importance of posttranslational and translational modifications in maintaining hepatic rhythmicity. The hepatic proteome also shows some dependence on the circadian clock machinery as livers from Clock mutant mice and mPer2^ldc mice (11) show dampened oscillatory activity for some proteins (190).

Recent work on the hepatic circadian clock has led to an emerging theme in the circadian field; several circadian clock proteins actually have numerous intracellular roles in addition to contributing to the classical loop of FIGURE 2. As many genes show liver-specific oscillations, it is perhaps not surprising that some members of the clock machinery interact with non-core clock proteins such as tissue-specific nuclear factors (FIGURE 5). Nuclear receptors are central to liver metabolism, regulating genes involved in glucose and lipid metabolism among others (251). Recently, PER2 and CRY1 have been observed to have functions independent of their CLOCK:BMAL1 repression (86, 255). Thus far, PER2 seems particularly promiscuous, binding to PPARγ, PPARα, and REV-ERBα (87, 206), thereby controlling white adipose and liver tissue metabolic processes. PER2 appears to be unique among the PER proteins in its ability to bind core clock machinery as well as these nuclear receptors. Studies in the last decade have confirmed the circadian rhythmicity of numerous nuclear receptors, the oscillations of which show tissue specificity in some cases (250).

Figure 5. — Circadian clock proteins engage in additional functions when they collaborate with proteins outside of the core clock machinery. While CLOCK:BMAL1 activate numerous clock output genes, CRY1 and PER proteins bind to other nuclear receptors or intracellular proteins to regulate disparate functions such as adipogenesis and gluconeogenesis.

CRY1 also appears to have dual roles in regulating the hepatic clock. In addition to its role as a negative-feedback regulator of CLOCK:BMAL1-dependent gene transcription, recently demonstrated is its ability to suppress hepatic gluconeogenesis. CRY1 protein oscillates, with elevated levels in the liver occurring during the nighttime in nocturnal rodents. CRY1 appears to block cAMP production in the liver, probably by binding to G_sα, thereby preventing coupling of G protein-coupled receptors to adenylyl cyclases (255). As forskolin, a general adenylyl cyclase activator, is able to overcome inhibition by CRY1 of gluconeogenic gene expression [phosphoenolpyruvate kinase (PEPCK) and glucose-6-phosphatase (G-6-Pase), specificially] in the presence of more than one G protein-coupled receptor, it is possible that CRY1 is a general inhibitor of G_sα.

3. Circadian rhythmicity in metabolic peripheral tissues

Most tissues display circadian rhythms. In addition to the hepatic clock, other metabolic tissues show strong oscillations in gene expression. Adipose tissue is among these. Adipocytes host molecular clocks, and their proliferation is under the influence of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ), the expression of which oscillates in adipose tissue and by the circadian protein REV-ERBα, which suppresses anti-adipogenic genes (reviewed in Ref. 20). Adipose tissue is particularly relevant to metabolic homeostasis because leptin and adiponectin, two hormones central to the control of metabolism and cardiovascular disease, are released from adipocytes in a circadian fashion. The adipokine adiponectin is also released from adipocytes, and its plasma levels fall during the nighttime hours (78). This circadian property of adiponectin release has been a topic of interest as adiponectin, also known for its anti-inflammatory and antiatherogenic properties, is tightly linked to metabolism and body weight regulation in humans. For example, decreases in adiponectin have been observed in individuals with disorders associated with insulin resistance including obesity and type 2 diabetes (101, 242). The oscillation of adiponectin may also be important for target tissues such as muscle where adiponectin signaling affects the number of mitochondria. Recent studies looking at adiponectin signaling in muscle show that loss of the adiponectin receptor 1 in muscle results in a decrease in exercise capacity (107). Mediated through AMPK and SIRT1 (two proteins that contribute to circadian rhythmicity), adiponectin appears to modulate muscle insulin sensitivity by modulating both PGC-1α expression (via CaMK and CREB) and its activity (via SIRT1-mediated deacetylation). These rodent studies compliment what is seen in humans, namely, a reduction in adiponectin receptor 1 and PGC-1α activity in individuals with type 2 diabetes (158).

Leptin secretion by adipocytes is also a circadian regulated event. Leptin's contribution to body weight regulation was first observed in the ob/ob and db/db mice, two obese, mutant mice generated at Jackson laboratories (31, 104, 106). Subsequent studies revealed that the obese (ob) gene was a leptin-encoding gene, and db/db mice were found to lack the leptin receptor (28, 256). These leptin-deficient mice are hyperphagic, show mild hyperglycemia and severe obesity, and serve as a model for type 2 diabetes. While altered leptin signaling has accounted for only a small percentage of human obesity, its link to circadian rhythms may contribute to the metabolic physiology of these individuals. In humans, plasma leptin levels oscillate with a maximum level occurring in the late night and early morning hours (inverse to adiponectin). Leptin levels generally correlate with increased adiposity, and leptin levels fall after weight loss in both mice and humans (151). Leptin levels as well as oscillation amplitude are greatly enhanced in obese women compared with normal-weight control women (136).

Aside from the humoral oscillations generated by adipose tissue, recent work shows that PER2 plays a key role in adipocyte gene expression via a direct interaction with PPARγ (87). In adipose tissue, the binding of PER2 to PPARγ recruits it away from target gene promoters. Studies performed on Per2^−/− mice (10), which have reduced adiposity, show that in the absence of PER2, genes normally expressed in brown adipose tissue begin to be expressed in white adipose tissue (87), essentially transforming white adipose tissue into a highly oxidative, brown adipose-like tissue, enhancing energy output and thereby producing a lean mouse.

The pancreas hosts an autonomous clock, and recent work on pancreatic islet cells clocks demonstrates their importance in insulin production and blood glucose maintenance (189, 199). Specifically, elimination of Clock or Bmal1 function specifically in islet cells of the pancreas causes reduced glucose tolerance, impaired insulin secretion, and alterations in both the size and proliferation of islet cells (152). Importantly, insulin resistance in circadian mutant mice is dissociable from obesity as restoration of islet cell activity can relieve the symptom of insulin resistance in spite of persisting obesity (152).

As a regulator of fluid volume and mineral and electrolyte composition in the body, the kidney has also been studied in a circadian context. The renal tubular NHE3 gene (which encodes the Na⁺/H⁺ exchanger) is CLOCK:BMAL1 responsive, containing an E box that interacts directly with the CLOCK:BMAL1 complex (200). Furthermore, the circadian fluctuation of gene expression in the kidney appears to be both light and to a lesser extent, food responsive, although both appear to be necessary for rapid entrainment of the kidney clock (244). Less is known about the physiological consequences of circadian disruption in the kidney. Also a central regulator of fluid balance, the adrenal glands appear to be important physiological mediators of the clock. The adrenal gland releases among other molecules mineralocorticoids and glucocorticoids and thereby participates in glucocorticoid-responsive gene expression in the liver. Approximately 5% of the adrenal transcriptome is under control of the circadian clock (176, 177), and recent studies reveal that the among these are genes that contribute to aldosterone release and, therefore, blood pressure homeostasis (51).

C. Clock Gene Function Within Metabolic Tissues

An exciting pursuit in circadian physiology is how the individual clock genes function in different metabolic tissues. To better understand how proteins of the circadian clock contribute to metabolism in metabolic tissues, a number of mutant and transgenic mouse strains have been studied, resulting in a better resolution picture of how circadian and metabolic processes interact to control physiology.

Circadian rhythmicity within the central nervous system is highly resilient. Even when core components of the clock machinery are genetically disturbed, rhythms typically persist in LD and even DD conditions. This speaks to the persistence of the clock and also to the dependence organisms have on a system that can synchronize with the environment. While disruption of circadian rhythmicity in DD conditions occurs in genetically modified Bmal1 knockout rodents (23), both rodents and humans that harbor certain deletions in, overexpression of, or mutation in other clock genes have produced some (though less pronounced) alterations in the endogenous time-keeping capacities of the clock. More subtle but still debilitating disturbances include loss of rhythmicity in free-running conditions, impaired response to light shift paradigms (i.e., “jetlag” scenarios), and very advanced or delayed sleep cycles. Some of the transgenic and knockout animals made to address the role of circadian clock genes in vivo as well as their corresponding circadian and metabolic phenotypes (or lack thereof) are depicted in TABLE 2. The number of genetically modified mice demonstrating both circadian and metabolic abnormalities is growing and includes global and sometimes tissue-specific alternations in Bmal1, Clock, Npas2, and isoforms of the Ck1, Cry, Per, Pgc-1, Rev-erb, and Ror genes (23, 35, 41, 125, 130, 134, 152, 199, 233, 236, 258) (3, 12, 26, 29, 33, 42, 51, 54–56, 65, 85, 86, 92, 138, 140, 143, 146, 148, 175, 186, 188, 211, 219, 235, 248, 257).

Table 2.

Genetically modified circadian mutants and their corresponding circadian and metabolic phenotypes

Gene	Tissue-Specific Disruption?	Circadian Phenotype	Metabolic Phenotype
Bmal1 (Arntl)	No	Arrhythmia in DD, altered light response	Reduced activity in LD, reduced lifespan and accelerated aging
Bmal1 (Arntl)	Yes, pancreas		Impaired GT, reduced islet insulin secretion
Bmal1 (Arntl)	Yes, liver		Fasting-induced hypoglycemia
ClockΔ19	No	Long period in DD, then loss of rhythmicity	Increased serum TGA, impaired glucose sensitivity, obesity, low liver TG on high fat diet, reduced islet size and proliferation
Clock “deficient”	No	Slightly shorter period in DD, impaired light response and entrainment in LD	Partial diabetes insipidus, decrease in blood pressure, slight decrease in lifespan
Clock/Npas2	No	Arrhythmicity in DD
Ck1ε (tau mutation)	No	Shortened period in DD, impaired entrainment
Ck1δ mutant	No	Shortened period
Ck1δ	No	Embryonic lethality
Ck1δ	Yes, liver	Local period lengthening
Cry1, (Tg)	No
Cry1 (AP-Tg)	No	Long period in DD, splitting, impaired entrainment	Elevated glucose in serum and urine
Cry1/Cry2	No	Arrhythmia in DD, altered light response	Salt-sensitive hypertension
Noc (Nocturnin)	No		Resistant to diet-induced obesity (19)
Npas2	No	Enhanced adaptation to light entrainment	Higher nocturnal wheel running, delayed FAA activity
Per1	No	Shortened period in DD, impaired light response
Per2	No	Shortened period followed by arrhythmia in DD, impaired light response	Impaired lipid metabolism
Per3	No	Mild period shortening in DD	Increased adipose mass, glucose intolerance
Per1/Per2	No	Arrythmia in DD
Pgc-1α	No	Mildly longer period in DD	Resistance to HF diet-induced obesity, reduced thermogenesis, defective thermogenesis
Pgc-1β	No	Reduced activity in the dark	Reduced serum TG and FFA levels, elevated hepatic lipid accumulation during HF feeding
Rev-erbα	No	Mildly shortened activity period in DD, impaired light response	High plasma LDL, altered hepatic TGA levels, low bile acid accumulation
Rev-erbα, Rev-erbβ (inducible)	No	Advanced phase angle of entrainment, short period in DD	Increased circulating glucose and TGA levels, reduced circulating FFA
Rorα (staggerer sg/sg)	No	Mildly shortened period in DD	Increased HDL and hepatic TGA, accelerated development of atherosclerosis, resistance to HF diet-induced obesity
Rorβ	No	Long period in DD

Open in a new tab

The circadian mutation as well as the affected tissue is documented along with the resulting circadian phenotype. If metabolic phenotypes for the corresponding mutant animal have been observed, they are listed in the last column.

The Clock gene was originally identified in a screen designed to look for endogenous mutations that result in a circadian phenotype (236). The Clock^Δ19 animals were found to harbor a deletion in the Clock gene that involves a 51-amino acid deletion in the transactivation domain, a mutation that is now known to be antimorphic to CLOCK function (121). This Clock mutant mouse (or Clock^Δ19 mouse) has been well studied and is of particular interest from a metabolic perspective. Clock^Δ19 mice are obese on a high-fat diet, insulin resistant, and show altered plasma triglyceride levels on the two separate backgrounds studied (130, 174, 233). Interestingly, another metabolic phenotype caused by the Clock ^Δ19 mutation has also been observed. While in a C57/bL6 background, the Clock^Δ19 mutation confers obesity on a high-fat diet, Jcl:ICR background mice harboring the Clock^Δ19 mutation show no obesity (174), but show abnormal lipid partitioning. When fed a high-fat diet, the Clock mutation in an ICR background reduces hepatic triglyceride levels. Oscillations in serum FFA levels are ablated by this mutation, and under high-fat feeding conditions, serum FFA levels rise (130). While plasma glucose and triglycerides have been repeatedly observed to oscillate in WT animals, oscillations are disrupted in Clock^Δ19 mutant mice (197, 205, 210). The hypertriglyceridemia in Clock^Δ19 mice may be attributable to the inability of the circadian clock to adequately regulate diurnal variations in plasma triglycerides. Specifically, oscillating ApoB lipoprotein-carrying triglycerides depend on the microsomal triglyceride transfer protein (MTP) chaperone to shuttle between membranes. SHP (small heterodimer partner) regulates MTP, and the recent discovery of a functional CLOCK-responsive E box in SHP led to studies which revealed its diurnal variation and contribution to normal circadian fluctuations in plasma triglyceride levels (24, 179). Aberrant expression of other metabolism-regulating genes has also been observed in the Clock^Δ19 mice on one or the other background, including hypocretin neuropeptide precursor (Hcrt, which encodes for orexin A and orexin B), ghrelin, cocaine and amphetamine regulated transcript (Cart), fatty acid binding protein1 (Fabp1), acyl-CoA synthetase 4 (Acsl4), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), the low-density lipoprotein receptor (Ldlr), and cytochrome P-450 family 7 subfamily A polypeptide 1 (Cyp7a1) (reviewed in Ref. 129).

The Clock^Δ19 mouse demonstrates the global importance of CLOCK on metabolism, and subsequent studies have been undertaken to identify the function of CLOCK and other circadian clock genes in different areas of the brain and the periphery. Additional mouse models made to address the role of the CLOCK protein in vivo have revealed some initially surprising results. First, the complete loss of CLOCK protein does not induce arrhythmia (41), although explant experiments from Clock knockout animals also demonstrate a dependence of peripheral oscillators on CLOCK protein (43). Studies addressed to determine why the absence of clock protein is unable to perturb the brain's ability to tell time revealed that Npas2 (the Clock paralog which is highly expressed in the brain and able to bind to CLOCK's transcriptional partner, BMAL1) is able to compensate for CLOCK in the brain but not the periphery. The Clock/Npas2 double knockout animal, which has no functional CLOCK or NPAS2 protein show arrhythmia, as would be expected if the presence of either CLOCK or NPAS2 protein was essential for maintaining rhythmicity in tissues of the central nervous system (42). The Clock knockout mouse is not completely immune to disturbances in the brain's clock, however. These animals show an impaired response to light shifting. Specifically, while light exposure during the early night (ZT12–16) phase delays the circadian clock in WT animals, Clock knockout animals are not phase delayed by light exposure (41). CLOCK and NPAS2 both appear to contribute to sleep homeostasis. Clock mutant mice sleep less and show reduced rapid eye movement (REM) sleep recovery after sleep deprivation than their WT counterparts (165). NPAS2 also has an effect on neuronal energetics as the loss of NPAS2 produces alterations in sleep homeostasis, altering the electrophysiological properties of neurons after sleep deprivation (55, 74).

The phenotype of Bmal1 knockout mice is unique in that it is the only circadian mutant that harboring a single gene mutation, shows complete arrhythmia (23, 125). Bmal1 knockout mice are completely arrhythmic in DD and display a severe metabolic phenotype. The fat, muscle, bone, spleen, kidney, testis, heart, and lung of Bmal1 knockout animals all show an age-dependent reduction in size, which is consistent with their elevated ROS levels (125). Unlike WT animals, glucose and triglyceride levels do not oscillate in Bmal1 knockout animals, and while WT animals typically show a circadian rhythmicity in blood glucose recovery following insulin injection, such rhythmicity is absent in Bmal1 knockout mice, which show instead pronounced hypoglycemia around the clock in response to insulin (197). These knockouts also show impaired gluconeogenesis, probably due in part to the lack of oscillatory PEPCK activity in their hepatocytes.

The Cry1/Cry2 double knockout animals demonstrate the necessity for cryptochrome protein function in the circadian clock in the absence of zeitgebers. These animals show complete arrhythmia in free running conditions (235). These mutants also show disrupted rhythms after changes in the lighting conditions. This particular attribute of the Cry1/Cry2 double knockout animals was somewhat of a surprise at the time the experiments were done as cryptochromes were still thought to be the primary light sensors for the mammalian biological clock. [Since this time, the photopigment melanopsin has been demonstrated to be important for photosensitive retinal ganglion cells in relaying light-sensitive information to the brain (196).] In addition to the Cry1 and Cry2 knockout animals, Cry1 overexpression in vivo has also been used to address the role of Cry1 in circadian timekeeping. Two strains of overexpressing Cry1 mice have been made: Cry1 (Tg) animals, which overexpress WT mouse Cry1; and Cry1 (AP-Tg) animals, which overexpress a Cry1 mutant lacking a conserved cysteine proline motif (175). While mice overexpressing WT Cry1 show a normal circadian profile, Cry1 (AP-Tg) mice show long periods in free running conditions. Furthermore, Cry1 (AP-Tg) mice show elevated levels of serum and urine glucose. In addition to the high glucose levels, these mice show some common symptoms of diabetes mellitus, polydipsia and polyuria.

Cry1/Cry2 null mice show an additional metabolic phenotype not yet observed in other circadian mutants, that of salt-sensitive hypertension. Hypertension is a common malady in humans that substantially increases the risk of stroke and heart attack. There are a number of known risk factors for salt-sensitive hypertension including age, race, family history, tobacco use, stress, and physical inactivity. Relatively recent data reveal that an abnormal circadian rhythm may be added to the list. Specifically, Cry1/Cry2 mutant mice show a malfunctioning renin-angiotensin-aldosterone system (RAAS) resulting from the aberrant production of the mineralocorticoid aldosterone in the zona glomerulosa cells of the adrenal gland. The 3β-hydroxysteroid dehydrogenase-isomerase enzyme oxidoreductase family is required for aldosterone synthesis and is dysregulated in the adrenal gland of Cry1/Cry2 mutant mice. Expression of the Hsd3b6 isoform not only oscillates in WT animals but is elevated and void of oscillatory expression in the zona glomerulosa of Cry1/Cry2 mutant mice. It is still unclear why Cry1/Cry2 mutant mice show this phenotype. However, the derepression of CLOCK:BMAL1-mediated gene transcription in the absence of Cry1 may allow for enhanced clock output expression. There are binding sites for the CLOCK:BMAL1-responsive DBP gene in the promoter of Hsd3b6 which may facilitate its increased expression (FIGURE 6).

Figure 6. — Possible molecular mechanisms observed for the salt-sensitive hypertension observed in *Cry1/Cry2* double-knockout animals. Elevated DBP-mediated gene expression may be responsible in the *Cry1/Cry2* double-knockout animals for the elevated *Hsd3b6* observed in these animals.

While metabolic phenotypes are observed in the Bmal1 knockout mice as well as Clock^Δ19 animals, tissue-specific clock targeting has been insightful in understanding the ways in which circadian processes affect metabolism. Mice generated to lack Bmal1 in pancreatic islet cells only demonstrate the importance of the clock in insulin secretion. Islet cell-specific Bmal1 knockout mice have normal body weights and compositions but show elevated glucose levels in ad libitum conditions. In addition, these mutants have impaired glucose tolerance and reduced insulin secretion. Islet studies from these mice confirm the reduced insulin responsiveness to glucose, directly implicating the pancreas clock as a contributor to normal insulin sensitivity and protection against diabetes mellitus (152).

In addition to its role in insulin secretion, BMAL1 plays a unique role in adipose tissue development. BMAL1 contributes to the process of lipogenesis and adipocyte differentiation (214). Mouse embryonic fibroblasts lacking Bmal1 expression are unable to differentiate into adipocytes, a process that is at least partly recoverable by the adenoviral expression of Bmal1 (full recovery requires the exogenous addition of PPARγ ligand). Furthermore, metabolic labeling experiments of Bmal1-overexpressing adipocytes have demonstrated that the lipid synthesis activity in modified adipocytes is much higher, allowing the cells to accumulate unusually large lipid deposits (214).

Rodent knockouts of nocturnin, a circadian deadenylase that is expressed with high amplitude in the liver, show negligible circadian defects but rather exhibit remarkable changes in metabolism. Noc^−/− mice are resistant to diet-induced obesity, possibly due to decreased food absorption from the intestine (85). Lipogenic gene expression is reduced in Noc^−/− mice, correlating with a decrease in hepatocyte lipid accumulation.

IV. MOLECULAR RHYTHMICITY OF METABOLITES AND THEIR REGULATORY ENZYMES

The identification of molecular rhythms that link the clock to metabolism has rapidly expanded from what was known about those present in the nucleus (via the clock transcriptional machinery) to those occurring outside of the nucleus (167, 168). While many genes oscillate in expression, posttranslational modification of proteins provides an additional oscillatory, nonnuclear event that can create rhythmicity in enzymatic activity whether or not a corresponding gene transcript oscillates (162, 166, 168, 189, 190). While such events are unlikely to be completely independent of circadian nuclear transcriptional events, the evidence of rhythmicity beyond the level of transcription expands the arena for potential zeitgebers that assist in entrainment or maintenance of local circadian clocks.

A. Rhythmicity in Metabolic Enzymes

Rhythmicity within metabolic pathways relies on oscillations of the enzymes (or their activity) required for a particular metabolic pathway, fluctuations in metabolite production and concentration, or both. It is likely that both oscillations in gene expression, and protein stability as well as metabolite production or turnover work together to maintain rhythmicity within a pathway. An example of such a scenario can be observed in the case of oxidative stress and the mechanisms by which the body copes with increased levels of it. The oxidative stress theory of aging purports that the accumulation of ROS-induced damage within biologically important molecules during an organism's life leads to aging. Interestingly, many antioxidant enzymes oscillate in a circadian fashion and with a profile that meets the metabolic demands of a particular tissue. For example, during the dark phase, oxidative metabolism is at its highest in the brain of rodents. This corresponds with increased levels of lipid peroxides in the hippocampus. The highest levels of hippocampal catalase and glutathione peroxidase activity, however, are concomitant with nocturnal peaks in lipoperoxidation, a coordination that probably functions to protect this memory-encoding structure from extensive oxidative damage over time (72). In this situation, the mRNA, protein, and activity levels of catalase and glutathione peroxidase oscillate in a circadian fashion. Other enzymes, whose activity and/or expression oscillates in a profile that is consistent with circadian physiology, include those important for cholesterol metabolism, amino acid regulation, glucose metabolism, drug and toxin metabolism, and the citric acid cycle (reviewed in Ref. 39). These and other evidence supporting a circadian link to metabolism and aging will be discussed further.

1. Rhythms in enzyme expression

The expression of many metabolic enzymes appears to be under circadian control. Sometimes rhythmicity in enzyme abundance is due to oscillatory expression of its mRNA, but sometimes the mRNA doesn't oscillate while the protein does (190). This is likely due to the rhythmic stabilization or degradation of specific proteins. Regardless of the mechanism, the implications of rhythmic enzyme production are numerous. For example, the mRNA abundance of several mitochondrial complex I proteins oscillate (reviewed in Ref. 137). Interestingly, the expression within the SCN of ∼20 protein subunits involved in the respiratory chain reaches its peak just before dawn, this occurring just prior to the circadian peaks for neuronal firing in the region, when the metabolic state within SCN neurons would be at its highest (9, 180). Gene expression arrays have revealed robust circadian oscillations in genes involved in detoxification, stress response, and other metabolic proteins. Interestingly, the activity of some of these gene products is driven by NAD⁺ or NADP⁺. Examples include short-branched chain acyl CoA dehydrogenase, aldehyde dehydrogenase, and oxido reductase (25). Enzymes necessary for detoxification comprise a large number of cycling genes in the fly head, including six cytochrome P-450 proteins as well as glutathione-S-transferase. The fly body also hosts circadian oscillations in gene expression, including the oscillations of a number of redox-associated genes. Consistent with the Drosophila microarray data, in the rodent brain and liver, glutathione peroxidase production peaks in a circadian manner. This event is driven by melatonin and is quite possibly temporally organized to specifically scavenge for reactive oxygen species (ROS) as ROS abundance peaks just before glutathione peroxidase production reaches its highest (137). Other metabolism-associated genes also show circadian oscillations in expression. These include genes encoding the glucagon receptor, glucokinase, glucagon, Glut2, glucose-6-phosphate transport protein, pyruvate kinase, and pyruvate dehydrogenase (131, 132, 180). Other metabolic enzymes such as glucose-6-phosphatase, acetyl-CoA carboxylase, cytochrome oxidase, lactate dehydrogenase, fatty acid synthase, and glycogen phosphorylase have also been shown to be rhythmically expressed and/or activated (reviewed in Ref. 76). These data support the idea that the cellular metabolism is greatly influenced by the rhythmic production and activity of mitochondrial proteins. This cross-talk likely determines how the cell responds in a temporally restricted manner to DNA damage induced by accumulating oxidative stress.

Two enzymes that assist in translating the metabolic cues in the cell to the clock were recently shown to oscillate in expression. First, the enzyme that controls the rate-limiting step in the NAD⁺ salvage pathway, NAMPT, was shown to oscillate in a CLOCK:BMAL1- and SIRT1-dependent manner (163). This oscillation is potentially of significance for all NAD⁺-dependent biochemical processes as it could be one mechanism by which the circadian clock temporally controls all NAD⁺-dependent reactions. Second, the AMP-activated protein kinase (Ampk), an important mediator of metabolic signals, was shown to oscillate. Specifically, oscillations in one of its regulatory subunits, ampkβ2, occur in a circadian fashion and are likely responsible for the rhythmic nuclear translocation of AMPK where it has access to specific substrates including CRY1 (133). The oscillation of AMPK is important in linking circadian rhythms to metabolism as AMPK activity is a direct reflection of the cell's energy status.

The expression of serotonin N-acetyltransferase (Aanat) in the pineal is important for the rhythmic release of melatonin as it serves as the rate-limiting step in melatonin synthesis. The robust oscillation of this enzyme depends in large part on the yin-yang effect of CREB and CREM-mediated promoter activity (reviewed in Ref. 73). While cAMP activates CREB-mediated gene transcription at the Aanat promoter, cAMP can also inhibit expression of the enzyme through the protein ICER. ICER is generated by the use of an alternative promoter in the Crem gene, and it oscillates robustly in the pineal where it helps control melatonin output by repressing Aanat gene transcription (221). Interestingly, ICER can regulate its own transcription as it binds to a cAMP response elements in its promoter with high affinity. The control of melatonin by AANAT represents how oscillators on different levels coordinately control physiology (FIGURE 7). Melatonin is released in a circadian fashion by the pineal to control physiological events as disparate as heart rate and sleep homeostasis. This requires synchronization between individual oscillators of the pineal. Within each of these pineal clocks are oscillations in the transcription of genes involved in melatonin synthesis (i.e., Aanat). However, at the center of Aanat expression lie transcriptional regulators that generate oscillatory rhythms of activation or repression by regulating their own promoters (i.e., ICER). Thus melatonin-generated rhythms are supported by several levels of oscillating events that coordinate remarkably to control this circadian phenomenon.

Figure 7. — Coordination between large and small loops is necessary for circadian physiology. Neurons of the SCN undergo oscillations in depolarization, activation of the ERK/MAPK cascade and CREB activity, as well as oscillations in gene expression. In addition, several small molecules have been shown to oscillate, including cAMP and calcium. While the SCN indirectly controls the oscillation of humoral factors coming from other tissues such as the pineal and adrenal cortex, continuity within the SCN is mediated by loops within VIP and AVP-expressing neurons. Other tissues also maintain circadian output via positive- and negative-feedback loops within cells that make up different compartments of the tissue. The arcuate nucleus is one such example, where NPY/AgRP-expressing and POMC-expressing neurons communicate in an oscillatory way to convey signals to the body after ghrelin release from the periphery and binding in the region. Oscillations in centrally released humoral factors control the circadian release of factors from the periphery, such as ghrelin, leptin, insulin, and glucose, and these in turn regulate brain function. Molecular oscillations within individual neurons of the pineal include those of cAMP response element binding protein (CREB) activity; its negative regulator, ICER; and the rate-limiting enzyme in melatonin biosynthesis, AANAT. Melatonin, which is released in a circadian fashion from the pineal, is involved in feedback regulation of the SCN where melatonin receptors are abundantly expressed.

The plasminogen activator inhibitor type 1 (Pai-1), a key regulator of fibrinolysis, shows an oscillatory expression in plasma and tissues, and the peak hour coincides with the highest incidence of myocardial infarction and high blood pressure. Pai-1 is regulated in part by REV-ERBα-mediated repression and therefore is directly subject to regulation by the clock machinery (240). High levels of PAI-1 are directly related to increased thrombosis, and elevated levels of PAI-1 have been observed in the atheroma taken from patients with type 2 diabetes (218).

2. Rhythms in enzymatic activity

Not all rhythmicity in enzyme activity is driven by oscillations in gene expression for that enzyme. On the contrary, some enzymes show oscillatory activity in the absence of oscillatory expression. For example, activity of the NAD⁺-dependent poly(ADP-ribose) polymerase 1, (PARP-1, an ADP ribosyltransferase) oscillates in a circadian manner, while its abundance appears relatively constant over the 24-h cycle (7). While known to participate in the plant circadian clock (49), recent evidence that its activity is important for the mammalian clock underscores the importance of fluctuations in NAD⁺/NADH for mammalian circadian physiology. Not only does auto-ADP-ribosylation of PARP-1 occur in a circadian fashion, peaking in the early rest period of nocturnal rodent liver, but PARP-1 directly binds to and poly(ADP-ribosyl)ates CLOCK in a circadian fashion, thereby modulating CLOCK:BMAL1 DNA binding affinity. Interestingly, Parp-1 knockout rodents are impaired in their ability to entrain to food, and while FAA activity appears to be normal, locomotion during the animals' active period is significantly increased in PARP-1 knockout mice (7).

Posttranslational modifications of enzymes are often important regulators of their activity. Protein acetylation is one such modification that has been observed to modulate protein activity. Numerous acetylated proteins have been assessed by proteomic studies, and such studies show that many of these acetylated sites are highly conserved between rodents and humans. Across different tissues, however, the location of these acetylation events can be quite disparate. Interestingly, numerous proteins involved in metabolic enzymes are acetylated. For example, PEPCK is subject to both transcriptional regulation and the posttranslational modification of acetylation. Acetylation of PEPCK appears to be related to the blood glucose levels and functions to control the rate of PEPCK turnover in the cell by triggering ubiquitination and degradation of the protein (109). While its acetylation has not been looked at in the context of circadian rhythmicity, its acetylation is likely circadian as glucose levels undergo circadian rhythmicity. PEPCK is acetylated by p300, an event that is counteracted by the sirtuin protein family member SIRT2 (109). Interestingly, many metabolic enzymes are acetylated based on fluctuations in intracellular glucose or acetate levels. As acetylation is directly linked to the circadian clock by the sirtuins among other HDACs, it is surmisable that posttranslational modification of these proteins occurs in a circadian fashion to accomplish the roles required of them throughout the circadian cycle. CLOCK may contribute to the circadian cycle of acetylation and deacetylation as its role as a HAT implicates it in direct regulation of its protein targets (50).

AMPK is an important mediator of metabolic signals, and its activity appears to be circadian (40). Recently, using mass spectrometry and bioinformatics, CRY1 protein was found to be directly phosphorylated by AMPK. This phosphorylation event by AMPK is critical for CRY1 turnover in vitro and in vivo and is therefore necessary for normal circadian rhythmicity. This link provides yet another example of the connection between the metabolic state of the cell and circadian gene transcription, in which AMPK acts as a chemical sensor for the cell (133).

B. Rhythmic Metabolite Production and Use

While a few individual metabolites have been shown to oscillate in vivo and in vitro, studies are beginning to focus on more global oscillations within the metabolome. This approach is important because if food can entrain peripheral clocks, it is likely that numerous metabolites that occur as a result of or in preparation for food digestion act as potent zeitgebers in and of themselves. Studies addressing the role of the circadian clock in controlling metabolite levels demonstrate that much of the liver metabolome is under circadian control, for example. Many metabolites oscillate in a circadian fashion, and the oscillation of some metabolites appears to be largely dependent on the expression of Clock (60). Large-scale mining of the literature has been instrumental in mapping these circadian metabolites amid the backdrop of their intracellular surroundings. For example, maps have now been created for circadian (and non-circadian)-controlled metabolites, which incorporate data from multiple sources such as those containing data on circadian gene oscillation of metabolite-producing and/or -degrading enzymes (103), high-affinity transcription factor binding sites for metabolic enzymes (34, 245), and the metabolite's own interacting metabolites (60, 114–116). Such networks can be visualized on an interactive database, http://circadiomics.igb.uci.edu/, which is freely available. As large-scale metabolomics becomes increasingly used, the creation of metabolite datasets will be informative with regard to how small metabolites reciprocally interact with the molecular components of the circadian clock. Metabolites representing numerous metabolic pathways appear to be under circadian control, with amino acid and xenobiotic metabolites tending to peak at night in nocturnal rodents and carbohydrate, lipid, and nucleotide metabolites peaking during the rest period (60) While over half of the metabolome may be under circadian influence, other studies in humans which have eliminated circadian activities (such as sleeping, diurnal eating patterns, and activity) from test subjects reveal that a remarkable 15% of the metabolome still remains under circadian control (36). The oscillations of numerous amino acids and urea cycle metabolites appear to be rigidly tied to the circadian clock and have now been reported in several studies (36, 60, 108, 155).

Additional studies focused on the oscillatory nature of specific metabolites have been revealing in how small biochemicals might function as zeitgebers for cells. For example, oscillation of NAD⁺ has pleiotropic effects in the cell and feeds back into the clock system via CLOCK:BMAL1-mediated gene transcription (163, 189). Within the mitochondria, ATP and NAD⁺ are used as carrier molecules for oxidation-reduction reactions. These carrier molecules are essential for cellular energy balance. For example, the release of electrons and a hydrogen atom off of substrate molecules are picked up by NAD⁺ and ultimately used by the cell to generate additional ATP and to drive ATP-dependent reactions. NAD⁺, which is generated from niacin, participates as a coenzyme in numerous cellular dehydrogenase reactions (such as the β-oxidation of fatty acids or the Krebs cycle). The role of NAD⁺ as a carrier molecule is essential for the production and maintenance of energy stores. In addition to its role in ATP generation, NAD⁺ also provides the ADP-ribose substrate necessary for the ADP ribosylation of target proteins. Prolonged increases in the activity of the NAD⁺-dependent ribosylating enzyme, poly(ADP-ribose) polymerase-1 (PARP-1), can deplete the cell of NAD⁺, ultimately causing cell death (30, 90, 119). The recent observation that NAD⁺ oscillates in a circadian manner brings to the forefront a direct link between energy stores and the circadian clock. NAD⁺ oscillations probably contribute, at least in part, to the oscillations observed in CLOCK:BMAL1 binding, PARP activity, and cyclic ADP-ribose (cADPR) production.

The small molecule cADPR, which is produced from NAD⁺ by ADP-ribosyl cyclases, has been reported to oscillate in a circadian fashion. cADPR serves as a ligand for the type 3 ryanodine receptors, generating cytosolic calcium release in plants and animal cells (89). While recent data suggest an absence of cADPR oscillatory activity in some situations (247), it has previously been reported to be synthesized in a circadian fashion in Arabidopsis where it controls the abundance of Clock gene expression (49). The dependence of cADPR production on cellular NAD⁺ levels is yet another example of how oscillations in metabolites feedback on the clock system and thereby integrate cellular metabolism in the circadian clock.

A recently discovered function of the CRY protein appears to also depend on rhythmic metabolic factors. In Drosophila, CRY controls neuronal firing rate. ILNv neurons, which are light-detecting neurons of Drosophila pacemaker cells, depend on CRY for a rapid response to light (69). This is achieved through a redox-based flavin mechanism, which appears to induce CRY-dependent neuronal responses to blue light. This TIM-independent CRY response can be attenuated by the administration of an antagonist, which blocks the flavin binding site in CRY. Potassium channel conductance appears to molecularly couple flavin-bound CRY to alterations in membrane potential as inhibitor cocktail of both voltage-gated and inward-rectifying potassium channels blocks changes in membrane potential in response to blue light while saturating doses of tetrodotoxin do not. Whether flavin oscillates in the Drosophila pacemaker cells is not currently known; however, the activity of CRY in response to light oscillates in a metabolite-dependent way and suggests the oscillatory pattern of FAD itself. The oscillation of FAD in rodent liver suggests that its oscillation may be present in other tissues and organisms (60).

Another route of coupling between metabolite availability and the circadian clock was shown several years ago and involves the ability of NPAS2 to function as a gas sensor (48). Specifically, the PAS domain of the NPAS2 protein binds heme, enabling it to function as a carbon dioxide-sensitive transcription factor. That two enzymes involved in heme and CO biosynthesis are differentially expressed in regions of the brain highly expressing NPAS2 may be more than mere coincidence. The expression of aminolevalinic acid synthases (Alas), a rate-limiting enzyme in heme biosynthesis, oscillates in a circadian fashion. In addition, heme oxygenase 2 (HO-2) involved in CO generation is highly expressed in the forebrain, where high levels of NPAS2 are also observed. If NPAS2 is CO responsive, it may be that both the availability of CO as well as the oscillating mechanism for its production may directly affect the core clock output, namely, NPAS2:BMAL1 dimerization and activation of gene transcription. Interestingly, NPAS2 functions as more than just a CO sensor. Both heme-bound and heme-less NPAS2 PAS domains require a high NADPH/NADP ratio for sufficient DNA binding. Heme is also a ligand for REV-ERBα (187, 252), the interaction of which precipitates the recruitment of the NCoR/histone deacetylase 3 (HDAC3) corepressor complex that leads to the repression of PGC-1α expression. Itself a potent inducer of heme synthesis, PGC-1α provides a negative-feedback loop that maintains heme levels and regulates cellular energy metabolism (243). The contribution of NCoR to the circadian clock has been well demonstrated. NCoR and the HDAC3 complex are recruited to the Bmal1 promoter by REV-ERBα, a process that contributes to the intracellular levels of BMAL1 in the cell. The formation of this complex is necessary for normal circadian rhythmicity as well as the oscillation of numerous metabolic regulatory genes (4, 253).

As NAD⁺ signals to the cell that the energy state is low, so does AMP. When energy is burned, AMP is produced. Like NAD⁺, AMP concentration directly links energy to the circadian clock. When AMP levels are elevated, AMPK gets phosphorylated by liver kinase B1 (LKB1) (96). As previously discussed, AMPK was recently identified as playing a direct role in circadian regulation in the form of regulating the stability of CRY1 protein (133). Indeed, mice injected with AMPK activators show decreased levels of CRY1 in the liver, and the absence of LKB1 in the liver of mice allows CRY1 stabilization. AMPK phosphorylates CRY1, which causes CRY1 to bind to the protein to F-box and leucine-rich repeat protein 3 (Fbxl3). This F-box protein, which is part of the ubiquitin protein complex responsible for the phosphorylation-dependent degradation of proteins by ubiquitination, degrades both CRY1 and CRY2 (215). CRY1 degradation has the net effect of derepressing CLOCK target genes; however, AMP levels affect gene expression in a more global fashion, via its regulation of CRY1.

While the expression of numerous nuclear hormone receptors is known to oscillate, many do not oscillate. Regardless of receptor oscillation, a number of endogenous ligands for these receptors do oscillate in a circadian fashion and therefore contribute to the growing number of metabolites and biochemicals that may function as zeitgebers for the clock in different cells and tissues (216, 250, 251). In addition to heme, other nuclear receptor ligands appear to be under circadian regulation. Fatty acids, bile acids, prostaglandins, leukotrienes, vitamins, and hormones appear to be part of the dynamic circadian metabolome that contributes to circadian physiology (60). How these biochemicals function to generate circadian function is distinct and probably tissue specific. A better understanding of how the circadian metabolome changes in different nutrient conditions promises to be important for future understanding of how the energy state of the cell couples to the circadian clock.

V. FROM METABOLITES TO PHYSIOLOGY

There are several physiological circuits that draw attention to the reciprocal interaction of the circadian and metabolic programs in vivo. These include circuits between multiple tissues such as occur between the SCN and the pineal, or the SCN and adipose tissue. They also include feedback loops that rely on humoral signals for interplay such as occur between the gut and the hypothalamus, or the liver and the SCN. For example, the hypothalamus responds quickly to humoral signals released in a circadian fashion by the periphery (such as leptin or ghrelin) and, in turn, regulates the energy output of peripheral tissues. Within these larger systems circuits, however, smaller circuits exist, such as the internal feedback loops within tissues. This lower tier of circuitry includes positive and negative feedback between SCN network neurons (via VIP, for example) or reciprocal regulation of neurons of the arcuate nucleus (such as occurs between NPY/AgRP GABA-releasing neurons and their POMC counterparts). FIGURE 7 depicts a few of the circuits that operate within the context of broader circuits that are important for the maintenance of energy balance. Finally, subtissue level oscillations include the cellular feedback mechanisms necessary for maintenance of circadian physiology. These include the molecular players involved in the basic feedback loop of FIGURE 2, but also supporting oscillatory intracellular activity such as occurs during the CREB and CREM-mediated regulation of Aanat expression (see sect. IVA1). If these basic cellular oscillators are faulty, circadian physiology is compromised because communication on the systems level is supported by the rhythmic activity of single cell oscillators.

As the rise in metabolic disorders is occurring at an unprecedented rate, understanding how the circadian system affects metabolic homeostasis has been a focus of numerous research communities in the last century. Lifestyles that extend our options for work and activity outside of the conventional day correlate with increased metabolic malfunction. These studies are leading to the understanding that metabolism and circadian rhythms are tightly linked. The goal, therefore, is to gain further insights into how these processes converge and to provide useful environmental, behavioral, or pharmacological solutions that curb the rising rate of metabolic disorders associated with circadian disturbance.

GRANTS

Monetary support includes the following: National Institutes of Health Grants F32-DK-083881 (to K. Eckel-Mahan) as well as GM-081634 and AG-033888 (to P. Sassone-Corsi) and Sirtris Pharmaceuticals Grant SP-48984 (to P. Sassone-Corsi).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

ACKNOWLEDGMENTS

Address for reprint requests and other correspondence: P. Sassone-Corsi, Center for Epigenetics and Metabolism, Dept. of Biological Chemistry, University of California at Irvine, 340 Sprague Hall, Irvine, CA 92697-4625 (e-mail: psc@uci.edu).

REFERENCES

1. Abrahamson EE, Moore RY. Lesions of suprachiasmatic nucleus efferents selectively affect rest-activity rhythm. Mol Cell Endocrinol 252: 46–56, 2006 [DOI] [PubMed] [Google Scholar]
2. Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12: 540–550, 2002 [DOI] [PubMed] [Google Scholar]
3. Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC. MPer1 and mper2 are essential for normal resetting of the circadian clock. J Biol Rhythms 16: 100–104, 2001 [DOI] [PubMed] [Google Scholar]
4. Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, Avila J, Bucan M, Ahima RS, Kaestner KH, Lazar MA. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Antunes LC, Levandovski R, Dantas G, Caumo W, Hidalgo MP. Obesity and shift work: chronobiological aspects. Nutr Res Rev 23: 155–168, 2010 [DOI] [PubMed] [Google Scholar]
6. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317–328, 2008 [DOI] [PubMed] [Google Scholar]
7. Asher G, Reinke H, Altmeyer M, Gutierrez-Arcelus M, Hottiger MO, Schibler U. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142: 943–953, 2010 [DOI] [PubMed] [Google Scholar]
8. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nature Neurosci 8: 476–483, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Aujard F, Herzog ED, Block GD. Circadian rhythms in firing rate of individual suprachiasmatic nucleus neurons from adult and middle-aged mice. Neuroscience 106: 255–261, 2001 [DOI] [PubMed] [Google Scholar]
10. Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30: 525–536, 2001 [DOI] [PubMed] [Google Scholar]
11. Bae K, Lee K, Seo Y, Lee H, Kim D, Choi I. Differential effects of two period genes on the physiology and proteomic profiles of mouse anterior tibialis muscles. Molecules Cells 22: 275–284, 2006 [PubMed] [Google Scholar]
12. Bae K, Weaver DR. Light-induced phase shifts in mice lacking mPER1 or mPER2. J Biol Rhythms 18: 123–133, 2003 [DOI] [PubMed] [Google Scholar]
13. Bartness TJ, Song CK, Demas GE. SCN efferents to peripheral tissues: implications for biological rhythms. J Biol Rhythms 16: 196–204, 2001 [DOI] [PubMed] [Google Scholar]
14. Batsis JA, Nieto-Martinez RE, Lopez-Jimenez F. Metabolic syndrome: from global epidemiology to individualized medicine. Clin Pharmacol Ther 82: 509–524, 2007 [DOI] [PubMed] [Google Scholar]
15. Bechtold DA, Brown TM, Luckman SM, Piggins HD. Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling. Am J Physiol Regul Integ Comp Physiol 294: R344–R351, 2008 [DOI] [PubMed] [Google Scholar]
16. Begriche K, Sutton GM, Fang J, Butler AA. The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin-3 receptors? Obes Rev 10 Suppl 2: 14–24, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Belden WJ, Dunlap JC. SIRT1 is a circadian deacetylase for core clock components. Cell 134: 212–214, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295: 1070–1073, 2002 [DOI] [PubMed] [Google Scholar]
19. Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Calcinaro F, Lolli C, Campbell P, Brunetti P, Gerich JE. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 33: 1150–1153, 1984 [DOI] [PubMed] [Google Scholar]
20. Bray MS, Young ME. Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes Rev 8: 169–181, 2007 [DOI] [PubMed] [Google Scholar]
21. Brown SA, Kowalska E, Dallmann R. (Re)inventing the circadian feedback loop. Dev Cell 22: 477–487, 2012 [DOI] [PubMed] [Google Scholar]
22. Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 11: 1535–1544, 1999 [DOI] [PubMed] [Google Scholar]
23. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009–1017, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez-Manrique RP, Orfila AM, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477: 482–485, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Ceriani MF, Hogenesch JB, Yanovsky M, Panda S, Straume M, Kay SA. Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J Neurosci 22: 9305–9319, 2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Cermakian N, Monaco L, Pando MP, Dierich A, Sassone-Corsi P. Altered behavioral rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene. EMBO J 20: 3967–3974, 2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet 26: 97–102, 2000 [DOI] [PubMed] [Google Scholar]
28. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491–495, 1996 [DOI] [PubMed] [Google Scholar]
29. Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, Ditacchio L, Atkins AR, Glass CK, Liddle C, Auwerx J, Downes M, Panda S, Evans RM. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Cipriani G, Rapizzi E, Vannacci A, Rizzuto R, Moroni F, Chiarugi A. Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem 280: 17227–17234, 2005 [DOI] [PubMed] [Google Scholar]
31. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141–148, 1978 [DOI] [PubMed] [Google Scholar]
32. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome. Endocr Rev 29: 777–822, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Costa MJ, So AY, Kaasik K, Krueger KC, Pillsbury ML, Fu YH, Ptacek LJ, Yamamoto KR, Feldman BJ. Circadian rhythm gene period 3 is an inhibitor of the adipocyte cell fate. J Biol Chem 286: 9063–9070, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Daily K, Patel VR, Rigor P, Xie X, Baldi P. MotifMap: integrative genome-wide maps of regulatory motif sites for model species. BMC Bioinformatics 12: 495, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Dallmann R, DeBruyne JP, Weaver DR. Photic resetting and entrainment in CLOCK-deficient mice. J Biol Rhythms 26: 390–401, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci USA 109: 2625–2629, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14: 2950–2961, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Dardente H, Cermakian N. Molecular circadian rhythms in central and peripheral clocks in mammals. Chronobiol Int 24: 195–213, 2007 [DOI] [PubMed] [Google Scholar]
39. Davidson AJ, Castanon-Cervantes O, Stephan FK. Daily oscillations in liver function: diurnal vs circadian rhythmicity. Liver Int 24: 179–186, 2004 [DOI] [PubMed] [Google Scholar]
40. Davies SP, Carling D, Munday MR, Hardie DG. Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur J Biochem 203: 615–623, 1992 [DOI] [PubMed] [Google Scholar]
41. DeBruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM. A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50: 465–477, 2006 [DOI] [PubMed] [Google Scholar]
42. DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nature Neurosci 10: 543–545, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
43. DeBruyne JP, Weaver DR, Reppert SM. Peripheral circadian oscillators require CLOCK. Curr Biol 17: R538–539, 2007 [DOI] [PubMed] [Google Scholar]
44. Di Lorenzo L, De Pergola G, Zocchetti C, L'Abbate N, Basso A, Pannacciulli N, Cignarelli M, Giorgino R, Soleo L. Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry. Int J Obes Relat Metab Disord 27: 1353–1358, 2003 [DOI] [PubMed] [Google Scholar]
45. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol 72: 517–549, 2010 [DOI] [PubMed] [Google Scholar]
46. Dickmeis T. Glucocorticoids and the circadian clock. J Endocrinol 200: 3–22, 2009 [DOI] [PubMed] [Google Scholar]
47. Dietrich MO, Horvath TL. Feeding signals and brain circuitry. Eur J Neurosci 30: 1688–1696, 2009 [DOI] [PubMed] [Google Scholar]
48. Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, McKnight SL. NPAS2: a gas-responsive transcription factor. Science 298: 2385–2387, 2002 [DOI] [PubMed] [Google Scholar]
49. Dodd AN, Gardner MJ, Hotta CT, Hubbard KE, Dalchau N, Love J, Assie JM, Robertson FC, Jakobsen MK, Goncalves J, Sanders D, Webb AA. The Arabidopsis circadian clock incorporates a cADPR-based feedback loop. Science 318: 1789–1792, 2007 [DOI] [PubMed] [Google Scholar]
50. Doi M, Hirayama J, Sassone-Corsi P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125: 497–508, 2006 [DOI] [PubMed] [Google Scholar]
51. Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O, Todo T, Tsutsui K, van der Horst GT, Okamura H. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nature Med 2009 [DOI] [PubMed] [Google Scholar]
52. Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. J Pineal Res 49: 14–22, 2010 [DOI] [PubMed] [Google Scholar]
53. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 27: 1453–1462, 2004 [DOI] [PubMed] [Google Scholar]
54. Dubrovsky YV, Samsa WE, Kondratov RV. Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging 2: 936–944, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Dudley CA, Erbel-Sieler C, Estill SJ, Reick M, Franken P, Pitts S, McKnight SL. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301: 379–383, 2003 [DOI] [PubMed] [Google Scholar]
56. Duez H, van der Veen JN, Duhem C, Pourcet B, Touvier T, Fontaine C, Derudas B, Bauge E, Havinga R, Bloks VW, Wolters H, van der Sluijs FH, Vennstrom B, Kuipers F, Staels B. Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology 135: 689–698, 2008 [DOI] [PubMed] [Google Scholar]
57. Duffield GE, Best JD, Meurers BH, Bittner A, Loros JJ, Dunlap JC. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol 12: 551–557, 2002 [DOI] [PubMed] [Google Scholar]
58. Eberly R, Feldman H. Obesity and Shift Work in the General Population. The Internet Journal of Allied Health and Nursing at Nova Southeastern University 8: 2010 [Google Scholar]
59. Eckel-Mahan K, Sassone-Corsi P. Metabolism control by the circadian clock and vice versa. Nature Struct Mol Biol 16: 462–467, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
60. Eckel-Mahan KL, Patel VR, Mohney RP, Vignola KS, Baldi P, Sassone-Corsi P. Coordination of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci USA 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
61. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 365: 1415–1428, 2005 [DOI] [PubMed] [Google Scholar]
62. Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M, Qin X, Xu Y, Pan M, Valekunja UK, Feeney KA, Maywood ES, Hastings MH, Baliga NS, Merrow M, Millar AJ, Johnson CH, Kyriacou CP, O'Neill JS, Reddy AB. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485: 459–464, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
63. Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 493: 63–71, 2005 [DOI] [PubMed] [Google Scholar]
64. Escobar C, Cailotto C, Angeles-Castellanos M, Delgado RS, Buijs RM. Peripheral oscillators: the driving force for food-anticipatory activity. Eur J Neurosci 30: 1665–1675, 2009 [DOI] [PubMed] [Google Scholar]
65. Etchegaray JP, Machida KK, Noton E, Constance CM, Dallmann R, Di Napoli MN, DeBruyne JP, Lambert CM, Yu EA, Reppert SM, Weaver DR. Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol Cell Biol 29: 3853–3866, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385: 165–168, 1997 [DOI] [PubMed] [Google Scholar]
67. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348: 1085–1095, 2003 [DOI] [PubMed] [Google Scholar]
68. Feige JN, Auwerx J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20: 303–309, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
69. Fogle KJ, Parson KG, Dahm NA, Holmes TC. CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science 331: 1409–1413, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
70. Fonken LK, Finy MS, Walton JC, Weil ZM, Workman JL, Ross J, Nelson RJ. Influence of light at night on murine anxiety- and depressive-like responses. Behav Brain Res 205: 349–354, 2009 [DOI] [PubMed] [Google Scholar]
71. Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ. Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci USA 107: 18664–18669, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
72. Fonzo LS, Golini RS, Delgado SM, Ponce IT, Bonomi MR, Rezza IG, Gimenez MS, Anzulovich AC. Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A-deficient rats. Hippocampus 19: 869–880, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
73. Foulkes NS, Whitmore D, Sassone-Corsi P. Rhythmic transcription: the molecular basis of circadian melatonin synthesis. Biol Cell 89: 487–494, 1997 [DOI] [PubMed] [Google Scholar]
74. Franken P, Dudley CA, Estill SJ, Barakat M, Thomason R, O'Hara BF, McKnight SL. NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. Proc Natl Acad Sci USA 103: 7118–7123, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
75. Froy O. Metabolism and circadian rhythms–implications for obesity. Endocr Rev 31: 1–24, 2010 [DOI] [PubMed] [Google Scholar]
76. Froy O. The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol 28: 61–71, 2007 [DOI] [PubMed] [Google Scholar]
77. Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms. Science 320: 1074–1077, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Gavrila A, Peng CK, Chan JL, Mietus JE, Goldberger AL, Mantzoros CS. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 88: 2838–2843, 2003 [DOI] [PubMed] [Google Scholar]
79. Gillette MU, Mitchell JW. Signaling in the suprachiasmatic nucleus: selectively responsive and integrative. Cell Tissue Res 309: 99–107, 2002 [DOI] [PubMed] [Google Scholar]
80. Glass JD, Guinn J, Kaur G, Francl JM. On the intrinsic regulation of neuropeptide Y release in the mammalian suprachiasmatic nucleus circadian clock. Eur J Neurosci 31: 1117–1126, 2010 [DOI] [PubMed] [Google Scholar]
81. Goel N, Stunkard AJ, Rogers NL, Van Dongen HP, Allison KC, O'Reardon JP, Ahima RS, Cummings DE, Heo M, Dinges DF. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms 24: 85–94, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Goldstein JL, Zhao TJ, Li RL, Sherbet DP, Liang G, Brown MS. Surviving starvation: essential role of the ghrelin-growth hormone axis. Cold Spring Harbor Symp Quantitative Biol 2011 [DOI] [PubMed] [Google Scholar]
83. Granados-Fuentes D, Prolo LM, Abraham U, Herzog ED. The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb. J Neurosci 24: 615–619, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
84. Granados-Fuentes D, Tseng A, Herzog ED. A circadian clock in the olfactory bulb controls olfactory responsivity. J Neurosci 26: 12219–12225, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
85. Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, Lourim D, Keller SR, Besharse JC. Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci USA 104: 9888–9893, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
86. Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, Amin RH, Granneman JG, Piomelli D, Leff T, Sassone-Corsi P. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab 12: 509–520, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
87. Grimaldi B, Nakahata Y, Sahar S, Kaluzova M, Gauthier D, Pham K, Patel N, Hirayama J, Sassone-Corsi P. Chromatin remodeling and circadian control: master regulator CLOCK is an enzyme. Cold Spring Harbor Symp Quantitative Biol 72: 105–112, 2007 [DOI] [PubMed] [Google Scholar]
88. Groop L. Genetics of the metabolic syndrome. Br J Nutr 83 Suppl 1: S39–48, 2000 [DOI] [PubMed] [Google Scholar]
89. Guse AH, da Silva CP, Berg I, Skapenko AL, Weber K, Heyer P, Hohenegger M, Ashamu GA, Schulze-Koops H, Potter BV, Mayr GW. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398: 70–73, 1999 [DOI] [PubMed] [Google Scholar]
90. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 96: 13978–13982, 1999 [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5: 253–295, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES. Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379: 736–739, 1996 [DOI] [PubMed] [Google Scholar]
93. Hannibal J, Ding JM, Chen D, Fahrenkrug J, Larsen PJ, Gillette MU, Mikkelsen JD. Pituitary adenylate cyclase activating peptide (PACAP) in the retinohypothalamic tract: a daytime regulator of the biological clock. Ann NY Acad Sci 865: 197–206, 1998 [DOI] [PubMed] [Google Scholar]
94. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi JC, Kelly JS, Maywood ES, Hastings MH. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109: 497–508, 2002 [DOI] [PubMed] [Google Scholar]
95. Hastings MH, Maywood ES, Reddy AB. Two decades of circadian time. J Neuroendocrinol 20: 812–819, 2008 [DOI] [PubMed] [Google Scholar]
96. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2: 28, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integ Comp Physiol 299: R711–R722, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Hegele RA, Pollex RL. Genetic and physiological insights into the metabolic syndrome. Am J Physiol Regul Integ Comp Physiol 289: R663–R669, 2005 [DOI] [PubMed] [Google Scholar]
99. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450: 1086–1090, 2007 [DOI] [PubMed] [Google Scholar]
100. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Jr, Alt FW, Kahn CR, Verdin E. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464: 121–125, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
101. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis Thrombosis Vasc Biol 20: 1595–1599, 2000 [DOI] [PubMed] [Google Scholar]
102. Hughes AT, Fahey B, Cutler DJ, Coogan AN, Piggins HD. Aberrant gating of photic input to the suprachiasmatic circadian pacemaker of mice lacking the VPAC2 receptor. J Neurosci 24: 3522–3526, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
103. Hughes M, Deharo L, Pulivarthy SR, Gu J, Hayes K, Panda S, Hogenesch JB. High-resolution time course analysis of gene expression from pituitary. Cold Spring Harbor Symp Quant Biol 72: 381–386, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
104. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science 153: 1127–1128, 1966 [DOI] [PubMed] [Google Scholar]
105. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141, 1997 [DOI] [PubMed] [Google Scholar]
106. Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Heredity 41: 317–318, 1950 [DOI] [PubMed] [Google Scholar]
107. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca²⁺ and AMPK/SIRT1. Nature 464: 1313–1319, 2010 [DOI] [PubMed] [Google Scholar]
108. Jeyaraj D, Scheer FA, Ripperger JA, Haldar SM, Lu Y, Prosdocimo DA, Eapen SJ, Eapen BL, Cui Y, Mahabeleshwar GH, Lee HG, Smith MA, Casadesus G, Mintz EM, Sun H, Wang Y, Ramsey KM, Bass J, Shea SA, Albrecht U, Jain MK. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab 15: 311–323, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
109. Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell 43: 33–44, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
110. Kaiya H, Kojima M, Hosoda H, Koda A, Yamamoto K, Kitajima Y, Matsumoto M, Minamitake Y, Kikuyama S, Kangawa K. Bullfrog ghrelin is modified by n-octanoic acid at its third threonine residue. J Biol Chem 276: 40441–40448, 2001 [DOI] [PubMed] [Google Scholar]
111. Kalsbeek A, Buijs RM, Engelmann M, Wotjak CT, Landgraf R. In vivo measurement of a diurnal variation in vasopressin release in the rat suprachiasmatic nucleus. Brain Res 682: 75–82, 1995 [DOI] [PubMed] [Google Scholar]
112. Kalsbeek A, Foppen E, Schalij I, Van Heijningen C, van der Vliet J, Fliers E, Buijs RM. Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate. PloS One 3: e3194, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
113. Kametani H, Kawamura H. Circadian rhythm of cortical acetylcholine release as measured by in vivo microdialysis in freely moving rats. Neurosci Lett 132: 263–266, 1991 [DOI] [PubMed] [Google Scholar]
114. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
115. Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34: D354–357, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
116. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40: D109–114, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
117. Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occupat Environ Med 58: 747–752, 2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
118. Karlsson BH, Knutsson AK, Lindahl BO, Alfredsson LS. Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health 76: 424–430, 2003 [DOI] [PubMed] [Google Scholar]
119. Kauppinen TM, Swanson RA. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145: 1267–1272, 2007 [DOI] [PubMed] [Google Scholar]
120. Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Speizer FE, Hennekens CH. Prospective study of shift work and risk of coronary heart disease in women. Circulation 92: 3178–3182, 1995 [DOI] [PubMed] [Google Scholar]
121. King DP, Vitaterna MH, Chang AM, Dove WF, Pinto LH, Turek FW, Takahashi JS. The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit. Genetics 146: 1049–1060, 1997 [DOI] [PMC free article] [PubMed] [Google Scholar]
122. Knutsson A. Health disorders of shift workers. Occupational Med 53: 103–108, 2003 [DOI] [PubMed] [Google Scholar]
123. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660, 1999 [DOI] [PubMed] [Google Scholar]
124. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280: 25196–25201, 2005 [DOI] [PubMed] [Google Scholar]
125. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20: 1868–1873, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
126. Krauchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. Neuropsychopharmacology 25: S92–96, 2001 [DOI] [PubMed] [Google Scholar]
127. Krieger DT, Hauser H, Krey LC. Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity. Science 197: 398–399, 1977 [DOI] [PubMed] [Google Scholar]
128. Kubo T, Oyama I, Nakamura T, Shirane K, Otsuka H, Kunimoto M, Kadowaki K, Maruyama T, Otomo H, Fujino Y, Matsumoto T, Matsuda S. Retrospective cohort study of the risk of obesity among shift workers: findings from the Industry-based Shift Workers' Health study, Japan. Occupat Environ Med 68: 327–331, 2011 [DOI] [PubMed] [Google Scholar]
129. Kudo T, Horikawa K, Shibata S. Circadian rhythms in the CNS and peripheral clock disorders: the circadian clock and hyperlipidemia. J Pharmacol Sci 103: 139–143, 2007 [DOI] [PubMed] [Google Scholar]
130. Kudo T, Tamagawa T, Kawashima M, Mito N, Shibata S. Attenuating effect of clock mutation on triglyceride contents in the ICR mouse liver under a high-fat diet. J Biol Rhythms 22: 312–323, 2007 [DOI] [PubMed] [Google Scholar]
131. La Fleur SE, Kalsbeek A, Wortel J, Fekkes ML, Buijs RM. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes 50: 1237–1243, 2001 [DOI] [PubMed] [Google Scholar]
132. La Fleur SE, Kalsbeek A, Wortel J, van der Vliet J, Buijs RM. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol 13: 1025–1032, 2001 [DOI] [PubMed] [Google Scholar]
133. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437–440, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
134. Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA 105: 15172–15177, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
135. Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, Sternglanz R. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA 97: 5807–5811, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
136. Langendonk JG, Pijl H, Toornvliet AC, Burggraaf J, Frolich M, Schoemaker RC, Doornbos J, Cohen AF, Meinders AE. Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss. J Clin Endocrinol Metab 83: 1706–1712, 1998 [DOI] [PubMed] [Google Scholar]
137. Langmesser S, Albrecht U. Life time-circadian clocks, mitochondria and metabolism. Chronobiol Int 23: 151–157, 2006 [DOI] [PubMed] [Google Scholar]
138. Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Sasso GL, Moschetta A, Schibler U. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol 7: e1000181, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
139. Leak RK, Card JP, Moore RY. Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport. Brain Res 819: 23–32, 1999 [DOI] [PubMed] [Google Scholar]
140. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
141. LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R. Stomach ghrelin-secreting cells as food-entrainable circadian clocks. Proc Natl Acad Sci USA 106: 13582–13587, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
142. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. Int J Biol Sci 7: 575–587, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
143. Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, Spiegelman BM. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278: 30843–30848, 2003 [DOI] [PubMed] [Google Scholar]
144. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418: 344–348, 2002 [DOI] [PubMed] [Google Scholar]
145. Liu C, Gillette MU. Cholinergic regulation of the suprachiasmatic nucleus circadian rhythm via a muscarinic mechanism at night. J Neurosci 16: 744–751, 1996 [DOI] [PMC free article] [PubMed] [Google Scholar]
146. Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447: 477–481, 2007 [DOI] [PubMed] [Google Scholar]
147. Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR, Geysen HM, Gaylinn BD, Thorner MO. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab 93: 1980–1987, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
148. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483–492, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
149. Lowrey PL, Takahashi JS. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet 5: 407–441, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
150. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371: 799–802, 1994 [DOI] [PubMed] [Google Scholar]
151. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med 1: 1155–1161, 1995 [DOI] [PubMed] [Google Scholar]
152. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466: 627–631, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
153. Martin B, Shin YK, White CM, Ji S, Kim W, Carlson OD, Napora JK, Chadwick W, Chapter M, Waschek JA, Mattson MP, Maudsley S, Egan JM. Vasoactive intestinal peptide-null mice demonstrate enhanced sweet taste preference, dysglycemia, and reduced taste bud leptin receptor expression. Diabetes 59: 1143–1152, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
154. Miller BH, McDearmon EL, Panda S, Hayes KR, Zhang J, Andrews JL, Antoch MP, Walker JR, Esser KA, Hogenesch JB, Takahashi JS. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA 104: 3342–3347, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
155. Minami Y, Kasukawa T, Kakazu Y, Iigo M, Sugimoto M, Ikeda S, Yasui A, van der Horst GT, Soga T, Ueda HR. Measurement of internal body time by blood metabolomics. Proc Natl Acad Sci USA 106: 9890–9895, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
156. Mistlberger RE. Food-anticipatory circadian rhythms: concepts and methods. Eur J Neurosci 30: 1718–1729, 2009 [DOI] [PubMed] [Google Scholar]
157. Moller M, Lund-Andersen C, Rovsing L, Sparre T, Bache N, Roepstorff P, Vorum H. Proteomics of the photoneuroendocrine circadian system of the brain. Mass Spectrometry Rev 29: 313–325, 2010 [DOI] [PubMed] [Google Scholar]
158. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet 34: 267–273, 2003 [DOI] [PubMed] [Google Scholar]
159. Nagai K, Nagai N, Shimizu K, Chun S, Nakagawa H, Niijima A. SCN output drives the autonomic nervous system: with special reference to the autonomic function related to the regulation of glucose metabolism. Prog Brain Res 111: 253–272, 1996 [DOI] [PubMed] [Google Scholar]
160. Nagai K, Nagai N, Sugahara K, Niijima A, Nakagawa H. Circadian rhythms and energy metabolism with special reference to the suprachiasmatic nucleus. Neurosci Biobehav Rev 18: 579–584, 1994 [DOI] [PubMed] [Google Scholar]
161. Nakahata Y, Grimaldi B, Sahar S, Hirayama J, Sassone-Corsi P. Signaling to the circadian clock: plasticity by chromatin remodeling. Curr Opin Cell Biol 19: 230–237, 2007 [DOI] [PubMed] [Google Scholar]
162. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P. The NAD^+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134: 329–340, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
163. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD⁺ salvage pathway by CLOCK-SIRT1. Science 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
164. Nakajima M, Imai K, Ito H, Nishiwaki T, Murayama Y, Iwasaki H, Oyama T, Kondo T. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308: 414–415, 2005 [DOI] [PubMed] [Google Scholar]
165. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, Turek FW. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 20: 8138–8143, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
166. O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320: 949–953, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
167. O'Neill JS, Reddy AB. Circadian clocks in human red blood cells. Nature 469: 498–503, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
168. O'Neill JS, van Ooijen G, Dixon LE, Troein C, Corellou F, Bouget FY, Reddy AB, Millar AJ. Circadian rhythms persist without transcription in a eukaryote. Nature 469: 554–558, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
169. O'Reardon JP, Peshek A, Allison KC. Night eating syndrome: diagnosis, epidemiology and management. CNS Drugs 19: 997–1008, 2005 [DOI] [PubMed] [Google Scholar]
170. O'Reardon JP, Ringel BL, Dinges DF, Allison KC, Rogers NL, Martino NS, Stunkard AJ. Circadian eating and sleeping patterns in the night eating syndrome. Obesity Res 12: 1789–1796, 2004 [DOI] [PubMed] [Google Scholar]
171. O'Reardon JP, Stunkard AJ, Allison KC. Clinical trial of sertraline in the treatment of night eating syndrome. Int J Eating Disorders 35: 16–26, 2004 [DOI] [PubMed] [Google Scholar]
172. Obrietan K, Impey S, Smith D, Athos J, Storm DR. Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274: 17748–17756, 1999 [DOI] [PubMed] [Google Scholar]
173. Obrietan K, Impey S, Storm DR. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature Neurosci 1: 693–700, 1998 [DOI] [PubMed] [Google Scholar]
174. Oishi K, Atsumi G, Sugiyama S, Kodomari I, Kasamatsu M, Machida K, Ishida N. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett 580: 127–130, 2006 [DOI] [PubMed] [Google Scholar]
175. Okano S, Akashi M, Hayasaka K, Nakajima O. Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice. Neurosci Lett 451: 246–251, 2009 [DOI] [PubMed] [Google Scholar]
176. Oster H, Damerow S, Hut RA, Eichele G. Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes. J Biol Rhythms 21: 350–361, 2006 [DOI] [PubMed] [Google Scholar]
177. Oster H, Damerow S, Kiessling S, Jakubcakova V, Abraham D, Tian J, Hoffmann MW, Eichele G. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab 4: 163–173, 2006 [DOI] [PubMed] [Google Scholar]
178. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3: 591–605, 2002 [DOI] [PubMed] [Google Scholar]
179. Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab 12: 174–186, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
180. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307–320, 2002 [DOI] [PubMed] [Google Scholar]
181. Pandit R, de Jong JW, Vanderschuren LJ, Adan RA. Neurobiology of overeating and obesity: the role of melanocortins and beyond. Eur J Pharmacol 660: 28–42, 2011 [DOI] [PubMed] [Google Scholar]
182. Parkes KR. Shift work and age as interactive predictors of body mass index among offshore workers. Scand J Work Environ Health 28: 64–71, 2002 [DOI] [PubMed] [Google Scholar]
183. Pendergast JS, Nakamura W, Friday RC, Hatanaka F, Takumi T, Yamazaki S. Robust food anticipatory activity in BMAL1-deficient mice. PloS One 4: e4860, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
184. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304: 110–115, 2004 [DOI] [PubMed] [Google Scholar]
185. Pitts S, Perone E, Silver R. Food-entrained circadian rhythms are sustained in arrhythmic Clk/Clk mutant mice. Am J Physiol Regul Integ Comp Physiol 285: R57–R67, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
186. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251–260, 2002 [DOI] [PubMed] [Google Scholar]
187. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nature Struct Mol Biol 14: 1207–1213, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
188. Ralph MR, Menaker M. A mutation of the circadian system in golden hamsters. Science 241: 1225–1227, 1988 [DOI] [PubMed] [Google Scholar]
189. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai SI, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD⁺ biosynthesis. Science 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
190. Reddy AB, Karp NA, Maywood ES, Sage EA, Deery M, O'Neill JS, Wong GK, Chesham J, Odell M, Lilley KS, Kyriacou CP, Hastings MH. Circadian orchestration of the hepatic proteome. Curr Biol 16: 1107–1115, 2006 [DOI] [PubMed] [Google Scholar]
191. Reddy AB, Maywood ES, Karp NA, King VM, Inoue Y, Gonzalez FJ, Lilley KS, Kyriacou CP, Hastings MH. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology 45: 1478–1488, 2007 [DOI] [PubMed] [Google Scholar]
192. Reilly T, Waterhouse J. Sports performance: is there evidence that the body clock plays a role? Eur J Appl Physiol 106: 321–332, 2009 [DOI] [PubMed] [Google Scholar]
193. Reiter RJ, Tan DX, Korkmaz A, Ma S. Obesity and metabolic syndrome: association with chronodisruption, sleep deprivation, and melatonin suppression. Ann Med 2011 [DOI] [PubMed] [Google Scholar]
194. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118, 2005 [DOI] [PubMed] [Google Scholar]
195. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol 22: 939–943, 2012 [DOI] [PubMed] [Google Scholar]
196. Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC, O'Hara BF. Role of melanopsin in circadian responses to light. Science 298: 2211–2213, 2002 [DOI] [PubMed] [Google Scholar]
197. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2: e377, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
198. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Jr, Vitiello MV, Zhdanova IV. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep 30: 1484–1501, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
199. Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54: 120–124, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
200. Saifur Rohman M, Emoto N, Nonaka H, Okura R, Nishimura M, Yagita K, van der Horst GT, Matsuo M, Okamura H, Yokoyama M. Circadian clock genes directly regulate expression of the Na⁺/H⁺ exchanger NHE3 in the kidney. Kidney Int 67: 1410–1419, 2005 [DOI] [PubMed] [Google Scholar]
201. Salgado-Delgado R, Angeles-Castellanos M, Buijs MR, Escobar C. Internal desynchronization in a model of night-work by forced activity in rats. Neuroscience 154: 922–931, 2008 [DOI] [PubMed] [Google Scholar]
202. Scheer FA, Van Doornen LJ, Buijs RM. Light and diurnal cycle affect autonomic cardiac balance in human: possible role for the biological clock. Auton Neurosci 110: 44–48, 2004 [DOI] [PubMed] [Google Scholar]
203. Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 43: 192–197, 2004 [DOI] [PubMed] [Google Scholar]
204. Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell 111: 919–922, 2002 [DOI] [PubMed] [Google Scholar]
205. Schlierf G, Dorow E. Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate-induction in man and their modification by nocturnal suppression of lipolysis. J Clin Invest 52: 732–740, 1973 [DOI] [PMC free article] [PubMed] [Google Scholar]
206. Schmutz I, Ripperger JA, Baeriswyl-Aebischer S, Albrecht U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev 24: 345–357, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
207. Schwartz MD, Urbanski HF, Nunez AA, Smale L. Projections of the suprachiasmatic nucleus and ventral subparaventricular zone in the Nile grass rat (Arvicanthis niloticus). Brain Res 1367: 146–161, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
208. Schwartz WJ, Reppert SM. Neural regulation of the circadian vasopressin rhythm in cerebrospinal fluid: a pre-eminent role for the suprachiasmatic nuclei. J Neurosci 5: 2771–2778, 1985 [DOI] [PMC free article] [PubMed] [Google Scholar]
209. Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci USA 103: 10224–10229, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
210. Seaman GV, Engel R, Swank RL, Hissen W. Circadian periodicity in some physicochemical parameters of circulating blood. Nature 207: 833–835, 1965 [DOI] [PubMed] [Google Scholar]
211. Shearman LP, Jin X, Lee C, Reppert SM, Weaver DR. Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol Cell Biol 20: 6269–6275, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
212. Sheward WJ, Maywood ES, French KL, Horn JM, Hastings MH, Seckl JR, Holmes MC, Harmar AJ. Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice. J Neurosci 27: 4351–4358, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
213. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12: 654–661, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
214. Shimba S, Ishii N, Ohta Y, Ohno T, Watabe Y, Hayashi M, Wada T, Aoyagi T, Tezuka M. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA 102: 12071–12076, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
215. Siepka SM, Yoo SH, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129: 1011–1023, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
216. Sladek FM. What are nuclear receptor ligands? Mol Cell Endocrinol 334: 3–13, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
217. Smith VM, Sterniczuk R, Phillips CI, Antle MC. Altered photic and non-photic phase shifts in 5-HT(1A) receptor knockout mice. Neuroscience 157: 513–523, 2008 [DOI] [PubMed] [Google Scholar]
218. Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation 97: 2213–2221, 1998 [DOI] [PubMed] [Google Scholar]
219. Sonoda J, Mehl IR, Chong LW, Nofsinger RR, Evans RM. PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 104: 5223–5228, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
220. Stanley BG, Leibowitz SF. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci 35: 2635–2642, 1984 [DOI] [PubMed] [Google Scholar]
221. Stehle JH, Foulkes NS, Pevet P, Sassone-Corsi P. Developmental maturation of pineal gland function: synchronized CREM inducibility and adrenergic stimulation. Mol Endocrinol 9: 706–716, 1995 [DOI] [PubMed] [Google Scholar]
222. Steinberger J, Daniels SR, Eckel RH, Hayman L, Lustig RH, McCrindle B, Mietus-Snyder ML. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 119: 628–647, 2009 [DOI] [PubMed] [Google Scholar]
223. Stephan FK, Swann JM, Sisk CL. Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 25: 346–363, 1979 [DOI] [PubMed] [Google Scholar]
224. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69: 1583–1586, 1972 [DOI] [PMC free article] [PubMed] [Google Scholar]
225. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science 291: 490–493, 2001 [DOI] [PubMed] [Google Scholar]
226. Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ. Extensive and divergent circadian gene expression in liver and heart. Nature 417: 78–83, 2002 [DOI] [PubMed] [Google Scholar]
227. Sujino M, Masumoto KH, Yamaguchi S, van der Horst GT, Okamura H, Inouye ST. Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of genetically arrhythmic mice. Curr Biol 13: 664–668, 2003 [DOI] [PubMed] [Google Scholar]
228. Sutton GM, Perez-Tilve D, Nogueiras R, Fang J, Kim JK, Cone RD, Gimble JM, Tschop MH, Butler AA. The melanocortin-3 receptor is required for entrainment to meal intake. J Neurosci 28: 12946–12955, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
229. Suwazono Y, Dochi M, Sakata K, Okubo Y, Oishi M, Tanaka K, Kobayashi E, Kido T, Nogawa K. A longitudinal study on the effect of shift work on weight gain in male Japanese workers. Obesity 16: 1887–1893, 2008 [DOI] [PubMed] [Google Scholar]
230. Tain YL, Huang LT, Lin IC, Lau YT, Lin CY. Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats. J Pineal Res 49: 390–398, 2011 [DOI] [PubMed] [Google Scholar]
231. Tanofsky-Kraff M, Yanovski SZ. Eating disorder or disordered eating? Non-normative eating patterns in obese individuals. Obesity Res 12: 1361–1366, 2004 [DOI] [PubMed] [Google Scholar]
232. Trumper BG, Reschke K, Molling J. Circadian variation of insulin requirement in insulin dependent diabetes mellitus the relationship between circadian change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon during euglycemia. Hormone metab Res 27: 141–147, 1995 [DOI] [PubMed] [Google Scholar]
233. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308: 1043–1045, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
234. Van Amelsvoort LG, Schouten EG, Kok FJ. Duration of shiftwork related to body mass index and waist to hip ratio. Int J Obes Relat Metab Disord 23: 973–978, 1999 [DOI] [PubMed] [Google Scholar]
235. Van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D, Hoeijmakers JH, Yasui A. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627–630, 1999 [DOI] [PubMed] [Google Scholar]
236. Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264: 719–725, 1994 [DOI] [PMC free article] [PubMed] [Google Scholar]
237. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci USA 106: 21453–21458, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
238. Vong L, Ye C, Yang Z, Choi B, Chua S, Jr, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71: 142–154, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
239. Vujovic N, Davidson AJ, Menaker M. Sympathetic input modulates, but does not determine, phase of peripheral circadian oscillators. Am J Physiol Regul Integ Comp Physiol 295: R355–R360, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
240. Wang J, Yin L, Lazar MA. The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. J Biol Chem 281: 33842–33848, 2006 [DOI] [PubMed] [Google Scholar]
241. Welsh DK, Logothetis DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14: 697–706, 1995 [DOI] [PubMed] [Google Scholar]
242. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86: 1930–1935, 2001 [DOI] [PubMed] [Google Scholar]
243. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha. Genes Dev 23: 2201–2209, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
244. Wu T, Ni Y, Dong Y, Xu J, Song X, Kato H, Fu Z. Regulation of circadian gene expression in the kidney by light and food cues in rats. Am J Physiol Regul Integ Comp Physiol 298: R635–R641, 2010 [DOI] [PubMed] [Google Scholar]
245. Xie X, Rigor P, Baldi P. MotifMap: a human genome-wide map of candidate regulatory motif sites. Bioinformatics 25: 167–174, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
246. Xu B, Kalra PS, Farmerie WG, Kalra SP. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, adipocyte leptin gene expression and secretion: effects of food restriction. Endocrinology 140: 2868–2875, 1999 [DOI] [PubMed] [Google Scholar]
247. Xu X, Graeff R, Xie Q, Gamble KL, Mori T, Johnson CH. Comment on “The Arabidopsis circadian clock incorporates a cADPR-based feedback loop”. Science 326: 230, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
248. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptacek LJ, Fu YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434: 640–644, 2005 [DOI] [PubMed] [Google Scholar]
249. Yan J, Wang H, Liu Y, Shao C. Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Computat Biol 4: e1000193, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
250. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear receptor expression links the circadian clock to metabolism. Cell 126: 801–810, 2006 [DOI] [PubMed] [Google Scholar]
251. Yang X, Lamia KA, Evans RM. Nuclear receptors, metabolism, the circadian clock. Cold Spring Harbor Symp Quant Biol 72: 387–394, 2007 [DOI] [PubMed] [Google Scholar]
252. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA. Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318: 1786–1789, 2007 [DOI] [PubMed] [Google Scholar]
253. Yin L, Wu N, Lazar MA. Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nuclear Receptor Signaling 8: e001, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
254. Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, Menaker M, Takahashi JS. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101: 5339–5346, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
255. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med 16: 1152–1156, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
256. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432, 1994 [DOI] [PubMed] [Google Scholar]
257. Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400: 169–173, 1999 [DOI] [PubMed] [Google Scholar]
258. Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, Bonny O, Firsov D. Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci USA 106: 16523–16528, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
259. Zulley J, Wever R, Aschoff J. The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature. Pflügers Arch 391: 314–318, 1981 [DOI] [PubMed] [Google Scholar]

[B1] 1. Abrahamson EE, Moore RY. Lesions of suprachiasmatic nucleus efferents selectively affect rest-activity rhythm. Mol Cell Endocrinol 252: 46–56, 2006 [DOI] [PubMed] [Google Scholar]

[B2] 2. Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12: 540–550, 2002 [DOI] [PubMed] [Google Scholar]

[B3] 3. Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC. MPer1 and mper2 are essential for normal resetting of the circadian clock. J Biol Rhythms 16: 100–104, 2001 [DOI] [PubMed] [Google Scholar]

[B4] 4. Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, Avila J, Bucan M, Ahima RS, Kaestner KH, Lazar MA. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5] 5. Antunes LC, Levandovski R, Dantas G, Caumo W, Hidalgo MP. Obesity and shift work: chronobiological aspects. Nutr Res Rev 23: 155–168, 2010 [DOI] [PubMed] [Google Scholar]

[B6] 6. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317–328, 2008 [DOI] [PubMed] [Google Scholar]

[B7] 7. Asher G, Reinke H, Altmeyer M, Gutierrez-Arcelus M, Hottiger MO, Schibler U. Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142: 943–953, 2010 [DOI] [PubMed] [Google Scholar]

[B8] 8. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nature Neurosci 8: 476–483, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B9] 9. Aujard F, Herzog ED, Block GD. Circadian rhythms in firing rate of individual suprachiasmatic nucleus neurons from adult and middle-aged mice. Neuroscience 106: 255–261, 2001 [DOI] [PubMed] [Google Scholar]

[B10] 10. Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30: 525–536, 2001 [DOI] [PubMed] [Google Scholar]

[B11] 11. Bae K, Lee K, Seo Y, Lee H, Kim D, Choi I. Differential effects of two period genes on the physiology and proteomic profiles of mouse anterior tibialis muscles. Molecules Cells 22: 275–284, 2006 [PubMed] [Google Scholar]

[B12] 12. Bae K, Weaver DR. Light-induced phase shifts in mice lacking mPER1 or mPER2. J Biol Rhythms 18: 123–133, 2003 [DOI] [PubMed] [Google Scholar]

[B13] 13. Bartness TJ, Song CK, Demas GE. SCN efferents to peripheral tissues: implications for biological rhythms. J Biol Rhythms 16: 196–204, 2001 [DOI] [PubMed] [Google Scholar]

[B14] 14. Batsis JA, Nieto-Martinez RE, Lopez-Jimenez F. Metabolic syndrome: from global epidemiology to individualized medicine. Clin Pharmacol Ther 82: 509–524, 2007 [DOI] [PubMed] [Google Scholar]

[B15] 15. Bechtold DA, Brown TM, Luckman SM, Piggins HD. Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling. Am J Physiol Regul Integ Comp Physiol 294: R344–R351, 2008 [DOI] [PubMed] [Google Scholar]

[B16] 16. Begriche K, Sutton GM, Fang J, Butler AA. The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin-3 receptors? Obes Rev 10 Suppl 2: 14–24, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B17] 17. Belden WJ, Dunlap JC. SIRT1 is a circadian deacetylase for core clock components. Cell 134: 212–214, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B18] 18. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295: 1070–1073, 2002 [DOI] [PubMed] [Google Scholar]

[B19] 19. Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Calcinaro F, Lolli C, Campbell P, Brunetti P, Gerich JE. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 33: 1150–1153, 1984 [DOI] [PubMed] [Google Scholar]

[B20] 20. Bray MS, Young ME. Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes Rev 8: 169–181, 2007 [DOI] [PubMed] [Google Scholar]

[B21] 21. Brown SA, Kowalska E, Dallmann R. (Re)inventing the circadian feedback loop. Dev Cell 22: 477–487, 2012 [DOI] [PubMed] [Google Scholar]

[B22] 22. Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 11: 1535–1544, 1999 [DOI] [PubMed] [Google Scholar]

[B23] 23. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009–1017, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B24] 24. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez-Manrique RP, Orfila AM, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477: 482–485, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B25] 25. Ceriani MF, Hogenesch JB, Yanovsky M, Panda S, Straume M, Kay SA. Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J Neurosci 22: 9305–9319, 2002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B26] 26. Cermakian N, Monaco L, Pando MP, Dierich A, Sassone-Corsi P. Altered behavioral rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene. EMBO J 20: 3967–3974, 2001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B27] 27. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet 26: 97–102, 2000 [DOI] [PubMed] [Google Scholar]

[B28] 28. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491–495, 1996 [DOI] [PubMed] [Google Scholar]

[B29] 29. Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, Ditacchio L, Atkins AR, Glass CK, Liddle C, Auwerx J, Downes M, Panda S, Evans RM. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B30] 30. Cipriani G, Rapizzi E, Vannacci A, Rizzuto R, Moroni F, Chiarugi A. Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem 280: 17227–17234, 2005 [DOI] [PubMed] [Google Scholar]

[B31] 31. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141–148, 1978 [DOI] [PubMed] [Google Scholar]

[B32] 32. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome. Endocr Rev 29: 777–822, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B33] 33. Costa MJ, So AY, Kaasik K, Krueger KC, Pillsbury ML, Fu YH, Ptacek LJ, Yamamoto KR, Feldman BJ. Circadian rhythm gene period 3 is an inhibitor of the adipocyte cell fate. J Biol Chem 286: 9063–9070, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B34] 34. Daily K, Patel VR, Rigor P, Xie X, Baldi P. MotifMap: integrative genome-wide maps of regulatory motif sites for model species. BMC Bioinformatics 12: 495, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B35] 35. Dallmann R, DeBruyne JP, Weaver DR. Photic resetting and entrainment in CLOCK-deficient mice. J Biol Rhythms 26: 390–401, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B36] 36. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci USA 109: 2625–2629, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B37] 37. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14: 2950–2961, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38] 38. Dardente H, Cermakian N. Molecular circadian rhythms in central and peripheral clocks in mammals. Chronobiol Int 24: 195–213, 2007 [DOI] [PubMed] [Google Scholar]

[B39] 39. Davidson AJ, Castanon-Cervantes O, Stephan FK. Daily oscillations in liver function: diurnal vs circadian rhythmicity. Liver Int 24: 179–186, 2004 [DOI] [PubMed] [Google Scholar]

[B40] 40. Davies SP, Carling D, Munday MR, Hardie DG. Diurnal rhythm of phosphorylation of rat liver acetyl-CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. Effects of high fat diets. Eur J Biochem 203: 615–623, 1992 [DOI] [PubMed] [Google Scholar]

[B41] 41. DeBruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM. A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50: 465–477, 2006 [DOI] [PubMed] [Google Scholar]

[B42] 42. DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nature Neurosci 10: 543–545, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B43] 43. DeBruyne JP, Weaver DR, Reppert SM. Peripheral circadian oscillators require CLOCK. Curr Biol 17: R538–539, 2007 [DOI] [PubMed] [Google Scholar]

[B44] 44. Di Lorenzo L, De Pergola G, Zocchetti C, L'Abbate N, Basso A, Pannacciulli N, Cignarelli M, Giorgino R, Soleo L. Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry. Int J Obes Relat Metab Disord 27: 1353–1358, 2003 [DOI] [PubMed] [Google Scholar]

[B45] 45. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol 72: 517–549, 2010 [DOI] [PubMed] [Google Scholar]

[B46] 46. Dickmeis T. Glucocorticoids and the circadian clock. J Endocrinol 200: 3–22, 2009 [DOI] [PubMed] [Google Scholar]

[B47] 47. Dietrich MO, Horvath TL. Feeding signals and brain circuitry. Eur J Neurosci 30: 1688–1696, 2009 [DOI] [PubMed] [Google Scholar]

[B48] 48. Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, McKnight SL. NPAS2: a gas-responsive transcription factor. Science 298: 2385–2387, 2002 [DOI] [PubMed] [Google Scholar]

[B49] 49. Dodd AN, Gardner MJ, Hotta CT, Hubbard KE, Dalchau N, Love J, Assie JM, Robertson FC, Jakobsen MK, Goncalves J, Sanders D, Webb AA. The Arabidopsis circadian clock incorporates a cADPR-based feedback loop. Science 318: 1789–1792, 2007 [DOI] [PubMed] [Google Scholar]

[B50] 50. Doi M, Hirayama J, Sassone-Corsi P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125: 497–508, 2006 [DOI] [PubMed] [Google Scholar]

[B51] 51. Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O, Todo T, Tsutsui K, van der Horst GT, Okamura H. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nature Med 2009 [DOI] [PubMed] [Google Scholar]

[B52] 52. Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. J Pineal Res 49: 14–22, 2010 [DOI] [PubMed] [Google Scholar]

[B53] 53. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 27: 1453–1462, 2004 [DOI] [PubMed] [Google Scholar]

[B54] 54. Dubrovsky YV, Samsa WE, Kondratov RV. Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging 2: 936–944, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B55] 55. Dudley CA, Erbel-Sieler C, Estill SJ, Reick M, Franken P, Pitts S, McKnight SL. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301: 379–383, 2003 [DOI] [PubMed] [Google Scholar]

[B56] 56. Duez H, van der Veen JN, Duhem C, Pourcet B, Touvier T, Fontaine C, Derudas B, Bauge E, Havinga R, Bloks VW, Wolters H, van der Sluijs FH, Vennstrom B, Kuipers F, Staels B. Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology 135: 689–698, 2008 [DOI] [PubMed] [Google Scholar]

[B57] 57. Duffield GE, Best JD, Meurers BH, Bittner A, Loros JJ, Dunlap JC. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol 12: 551–557, 2002 [DOI] [PubMed] [Google Scholar]

[B58] 58. Eberly R, Feldman H. Obesity and Shift Work in the General Population. The Internet Journal of Allied Health and Nursing at Nova Southeastern University 8: 2010 [Google Scholar]

[B59] 59. Eckel-Mahan K, Sassone-Corsi P. Metabolism control by the circadian clock and vice versa. Nature Struct Mol Biol 16: 462–467, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B60] 60. Eckel-Mahan KL, Patel VR, Mohney RP, Vignola KS, Baldi P, Sassone-Corsi P. Coordination of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci USA 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B61] 61. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 365: 1415–1428, 2005 [DOI] [PubMed] [Google Scholar]

[B62] 62. Edgar RS, Green EW, Zhao Y, van Ooijen G, Olmedo M, Qin X, Xu Y, Pan M, Valekunja UK, Feeney KA, Maywood ES, Hastings MH, Baliga NS, Merrow M, Millar AJ, Johnson CH, Kyriacou CP, O'Neill JS, Reddy AB. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485: 459–464, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B63] 63. Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 493: 63–71, 2005 [DOI] [PubMed] [Google Scholar]

[B64] 64. Escobar C, Cailotto C, Angeles-Castellanos M, Delgado RS, Buijs RM. Peripheral oscillators: the driving force for food-anticipatory activity. Eur J Neurosci 30: 1665–1675, 2009 [DOI] [PubMed] [Google Scholar]

[B65] 65. Etchegaray JP, Machida KK, Noton E, Constance CM, Dallmann R, Di Napoli MN, DeBruyne JP, Lambert CM, Yu EA, Reppert SM, Weaver DR. Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol Cell Biol 29: 3853–3866, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B66] 66. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385: 165–168, 1997 [DOI] [PubMed] [Google Scholar]

[B67] 67. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348: 1085–1095, 2003 [DOI] [PubMed] [Google Scholar]

[B68] 68. Feige JN, Auwerx J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20: 303–309, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B69] 69. Fogle KJ, Parson KG, Dahm NA, Holmes TC. CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science 331: 1409–1413, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B70] 70. Fonken LK, Finy MS, Walton JC, Weil ZM, Workman JL, Ross J, Nelson RJ. Influence of light at night on murine anxiety- and depressive-like responses. Behav Brain Res 205: 349–354, 2009 [DOI] [PubMed] [Google Scholar]

[B71] 71. Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ. Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci USA 107: 18664–18669, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B72] 72. Fonzo LS, Golini RS, Delgado SM, Ponce IT, Bonomi MR, Rezza IG, Gimenez MS, Anzulovich AC. Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A-deficient rats. Hippocampus 19: 869–880, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B73] 73. Foulkes NS, Whitmore D, Sassone-Corsi P. Rhythmic transcription: the molecular basis of circadian melatonin synthesis. Biol Cell 89: 487–494, 1997 [DOI] [PubMed] [Google Scholar]

[B74] 74. Franken P, Dudley CA, Estill SJ, Barakat M, Thomason R, O'Hara BF, McKnight SL. NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. Proc Natl Acad Sci USA 103: 7118–7123, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B75] 75. Froy O. Metabolism and circadian rhythms–implications for obesity. Endocr Rev 31: 1–24, 2010 [DOI] [PubMed] [Google Scholar]

[B76] 76. Froy O. The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol 28: 61–71, 2007 [DOI] [PubMed] [Google Scholar]

[B77] 77. Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms. Science 320: 1074–1077, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B78] 78. Gavrila A, Peng CK, Chan JL, Mietus JE, Goldberger AL, Mantzoros CS. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 88: 2838–2843, 2003 [DOI] [PubMed] [Google Scholar]

[B79] 79. Gillette MU, Mitchell JW. Signaling in the suprachiasmatic nucleus: selectively responsive and integrative. Cell Tissue Res 309: 99–107, 2002 [DOI] [PubMed] [Google Scholar]

[B80] 80. Glass JD, Guinn J, Kaur G, Francl JM. On the intrinsic regulation of neuropeptide Y release in the mammalian suprachiasmatic nucleus circadian clock. Eur J Neurosci 31: 1117–1126, 2010 [DOI] [PubMed] [Google Scholar]

[B81] 81. Goel N, Stunkard AJ, Rogers NL, Van Dongen HP, Allison KC, O'Reardon JP, Ahima RS, Cummings DE, Heo M, Dinges DF. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms 24: 85–94, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B82] 82. Goldstein JL, Zhao TJ, Li RL, Sherbet DP, Liang G, Brown MS. Surviving starvation: essential role of the ghrelin-growth hormone axis. Cold Spring Harbor Symp Quantitative Biol 2011 [DOI] [PubMed] [Google Scholar]

[B83] 83. Granados-Fuentes D, Prolo LM, Abraham U, Herzog ED. The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb. J Neurosci 24: 615–619, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B84] 84. Granados-Fuentes D, Tseng A, Herzog ED. A circadian clock in the olfactory bulb controls olfactory responsivity. J Neurosci 26: 12219–12225, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B85] 85. Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, Lourim D, Keller SR, Besharse JC. Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci USA 104: 9888–9893, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B86] 86. Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, Amin RH, Granneman JG, Piomelli D, Leff T, Sassone-Corsi P. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab 12: 509–520, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B87] 87. Grimaldi B, Nakahata Y, Sahar S, Kaluzova M, Gauthier D, Pham K, Patel N, Hirayama J, Sassone-Corsi P. Chromatin remodeling and circadian control: master regulator CLOCK is an enzyme. Cold Spring Harbor Symp Quantitative Biol 72: 105–112, 2007 [DOI] [PubMed] [Google Scholar]

[B88] 88. Groop L. Genetics of the metabolic syndrome. Br J Nutr 83 Suppl 1: S39–48, 2000 [DOI] [PubMed] [Google Scholar]

[B89] 89. Guse AH, da Silva CP, Berg I, Skapenko AL, Weber K, Heyer P, Hohenegger M, Ashamu GA, Schulze-Koops H, Potter BV, Mayr GW. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398: 70–73, 1999 [DOI] [PubMed] [Google Scholar]

[B90] 90. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 96: 13978–13982, 1999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B91] 91. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5: 253–295, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B92] 92. Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES. Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379: 736–739, 1996 [DOI] [PubMed] [Google Scholar]

[B93] 93. Hannibal J, Ding JM, Chen D, Fahrenkrug J, Larsen PJ, Gillette MU, Mikkelsen JD. Pituitary adenylate cyclase activating peptide (PACAP) in the retinohypothalamic tract: a daytime regulator of the biological clock. Ann NY Acad Sci 865: 197–206, 1998 [DOI] [PubMed] [Google Scholar]

[B94] 94. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi JC, Kelly JS, Maywood ES, Hastings MH. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109: 497–508, 2002 [DOI] [PubMed] [Google Scholar]

[B95] 95. Hastings MH, Maywood ES, Reddy AB. Two decades of circadian time. J Neuroendocrinol 20: 812–819, 2008 [DOI] [PubMed] [Google Scholar]

[B96] 96. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2: 28, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B97] 97. Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integ Comp Physiol 299: R711–R722, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B98] 98. Hegele RA, Pollex RL. Genetic and physiological insights into the metabolic syndrome. Am J Physiol Regul Integ Comp Physiol 289: R663–R669, 2005 [DOI] [PubMed] [Google Scholar]

[B99] 99. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450: 1086–1090, 2007 [DOI] [PubMed] [Google Scholar]

[B100] 100. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Jr, Alt FW, Kahn CR, Verdin E. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464: 121–125, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B101] 101. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis Thrombosis Vasc Biol 20: 1595–1599, 2000 [DOI] [PubMed] [Google Scholar]

[B102] 102. Hughes AT, Fahey B, Cutler DJ, Coogan AN, Piggins HD. Aberrant gating of photic input to the suprachiasmatic circadian pacemaker of mice lacking the VPAC2 receptor. J Neurosci 24: 3522–3526, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B103] 103. Hughes M, Deharo L, Pulivarthy SR, Gu J, Hayes K, Panda S, Hogenesch JB. High-resolution time course analysis of gene expression from pituitary. Cold Spring Harbor Symp Quant Biol 72: 381–386, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B104] 104. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science 153: 1127–1128, 1966 [DOI] [PubMed] [Google Scholar]

[B105] 105. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141, 1997 [DOI] [PubMed] [Google Scholar]

[B106] 106. Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Heredity 41: 317–318, 1950 [DOI] [PubMed] [Google Scholar]

[B107] 107. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca²⁺ and AMPK/SIRT1. Nature 464: 1313–1319, 2010 [DOI] [PubMed] [Google Scholar]

[B108] 108. Jeyaraj D, Scheer FA, Ripperger JA, Haldar SM, Lu Y, Prosdocimo DA, Eapen SJ, Eapen BL, Cui Y, Mahabeleshwar GH, Lee HG, Smith MA, Casadesus G, Mintz EM, Sun H, Wang Y, Ramsey KM, Bass J, Shea SA, Albrecht U, Jain MK. Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab 15: 311–323, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B109] 109. Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell 43: 33–44, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B110] 110. Kaiya H, Kojima M, Hosoda H, Koda A, Yamamoto K, Kitajima Y, Matsumoto M, Minamitake Y, Kikuyama S, Kangawa K. Bullfrog ghrelin is modified by n-octanoic acid at its third threonine residue. J Biol Chem 276: 40441–40448, 2001 [DOI] [PubMed] [Google Scholar]

[B111] 111. Kalsbeek A, Buijs RM, Engelmann M, Wotjak CT, Landgraf R. In vivo measurement of a diurnal variation in vasopressin release in the rat suprachiasmatic nucleus. Brain Res 682: 75–82, 1995 [DOI] [PubMed] [Google Scholar]

[B112] 112. Kalsbeek A, Foppen E, Schalij I, Van Heijningen C, van der Vliet J, Fliers E, Buijs RM. Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate. PloS One 3: e3194, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B113] 113. Kametani H, Kawamura H. Circadian rhythm of cortical acetylcholine release as measured by in vivo microdialysis in freely moving rats. Neurosci Lett 132: 263–266, 1991 [DOI] [PubMed] [Google Scholar]

[B114] 114. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B115] 115. Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34: D354–357, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B116] 116. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40: D109–114, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B117] 117. Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occupat Environ Med 58: 747–752, 2001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B118] 118. Karlsson BH, Knutsson AK, Lindahl BO, Alfredsson LS. Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health 76: 424–430, 2003 [DOI] [PubMed] [Google Scholar]

[B119] 119. Kauppinen TM, Swanson RA. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145: 1267–1272, 2007 [DOI] [PubMed] [Google Scholar]

[B120] 120. Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Speizer FE, Hennekens CH. Prospective study of shift work and risk of coronary heart disease in women. Circulation 92: 3178–3182, 1995 [DOI] [PubMed] [Google Scholar]

[B121] 121. King DP, Vitaterna MH, Chang AM, Dove WF, Pinto LH, Turek FW, Takahashi JS. The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit. Genetics 146: 1049–1060, 1997 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B122] 122. Knutsson A. Health disorders of shift workers. Occupational Med 53: 103–108, 2003 [DOI] [PubMed] [Google Scholar]

[B123] 123. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660, 1999 [DOI] [PubMed] [Google Scholar]

[B124] 124. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280: 25196–25201, 2005 [DOI] [PubMed] [Google Scholar]

[B125] 125. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20: 1868–1873, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B126] 126. Krauchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. Neuropsychopharmacology 25: S92–96, 2001 [DOI] [PubMed] [Google Scholar]

[B127] 127. Krieger DT, Hauser H, Krey LC. Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity. Science 197: 398–399, 1977 [DOI] [PubMed] [Google Scholar]

[B128] 128. Kubo T, Oyama I, Nakamura T, Shirane K, Otsuka H, Kunimoto M, Kadowaki K, Maruyama T, Otomo H, Fujino Y, Matsumoto T, Matsuda S. Retrospective cohort study of the risk of obesity among shift workers: findings from the Industry-based Shift Workers' Health study, Japan. Occupat Environ Med 68: 327–331, 2011 [DOI] [PubMed] [Google Scholar]

[B129] 129. Kudo T, Horikawa K, Shibata S. Circadian rhythms in the CNS and peripheral clock disorders: the circadian clock and hyperlipidemia. J Pharmacol Sci 103: 139–143, 2007 [DOI] [PubMed] [Google Scholar]

[B130] 130. Kudo T, Tamagawa T, Kawashima M, Mito N, Shibata S. Attenuating effect of clock mutation on triglyceride contents in the ICR mouse liver under a high-fat diet. J Biol Rhythms 22: 312–323, 2007 [DOI] [PubMed] [Google Scholar]

[B131] 131. La Fleur SE, Kalsbeek A, Wortel J, Fekkes ML, Buijs RM. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes 50: 1237–1243, 2001 [DOI] [PubMed] [Google Scholar]

[B132] 132. La Fleur SE, Kalsbeek A, Wortel J, van der Vliet J, Buijs RM. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol 13: 1025–1032, 2001 [DOI] [PubMed] [Google Scholar]

[B133] 133. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437–440, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B134] 134. Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA 105: 15172–15177, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B135] 135. Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, Sternglanz R. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA 97: 5807–5811, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B136] 136. Langendonk JG, Pijl H, Toornvliet AC, Burggraaf J, Frolich M, Schoemaker RC, Doornbos J, Cohen AF, Meinders AE. Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss. J Clin Endocrinol Metab 83: 1706–1712, 1998 [DOI] [PubMed] [Google Scholar]

[B137] 137. Langmesser S, Albrecht U. Life time-circadian clocks, mitochondria and metabolism. Chronobiol Int 23: 151–157, 2006 [DOI] [PubMed] [Google Scholar]

[B138] 138. Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Sasso GL, Moschetta A, Schibler U. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol 7: e1000181, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B139] 139. Leak RK, Card JP, Moore RY. Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport. Brain Res 819: 23–32, 1999 [DOI] [PubMed] [Google Scholar]

[B140] 140. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B141] 141. LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R. Stomach ghrelin-secreting cells as food-entrainable circadian clocks. Proc Natl Acad Sci USA 106: 13582–13587, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B142] 142. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. Int J Biol Sci 7: 575–587, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B143] 143. Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, Spiegelman BM. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278: 30843–30848, 2003 [DOI] [PubMed] [Google Scholar]

[B144] 144. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418: 344–348, 2002 [DOI] [PubMed] [Google Scholar]

[B145] 145. Liu C, Gillette MU. Cholinergic regulation of the suprachiasmatic nucleus circadian rhythm via a muscarinic mechanism at night. J Neurosci 16: 744–751, 1996 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B146] 146. Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447: 477–481, 2007 [DOI] [PubMed] [Google Scholar]

[B147] 147. Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR, Geysen HM, Gaylinn BD, Thorner MO. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab 93: 1980–1987, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B148] 148. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483–492, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B149] 149. Lowrey PL, Takahashi JS. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet 5: 407–441, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B150] 150. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371: 799–802, 1994 [DOI] [PubMed] [Google Scholar]

[B151] 151. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med 1: 1155–1161, 1995 [DOI] [PubMed] [Google Scholar]

[B152] 152. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466: 627–631, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B153] 153. Martin B, Shin YK, White CM, Ji S, Kim W, Carlson OD, Napora JK, Chadwick W, Chapter M, Waschek JA, Mattson MP, Maudsley S, Egan JM. Vasoactive intestinal peptide-null mice demonstrate enhanced sweet taste preference, dysglycemia, and reduced taste bud leptin receptor expression. Diabetes 59: 1143–1152, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B154] 154. Miller BH, McDearmon EL, Panda S, Hayes KR, Zhang J, Andrews JL, Antoch MP, Walker JR, Esser KA, Hogenesch JB, Takahashi JS. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci USA 104: 3342–3347, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B155] 155. Minami Y, Kasukawa T, Kakazu Y, Iigo M, Sugimoto M, Ikeda S, Yasui A, van der Horst GT, Soga T, Ueda HR. Measurement of internal body time by blood metabolomics. Proc Natl Acad Sci USA 106: 9890–9895, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B156] 156. Mistlberger RE. Food-anticipatory circadian rhythms: concepts and methods. Eur J Neurosci 30: 1718–1729, 2009 [DOI] [PubMed] [Google Scholar]

[B157] 157. Moller M, Lund-Andersen C, Rovsing L, Sparre T, Bache N, Roepstorff P, Vorum H. Proteomics of the photoneuroendocrine circadian system of the brain. Mass Spectrometry Rev 29: 313–325, 2010 [DOI] [PubMed] [Google Scholar]

[B158] 158. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet 34: 267–273, 2003 [DOI] [PubMed] [Google Scholar]

[B159] 159. Nagai K, Nagai N, Shimizu K, Chun S, Nakagawa H, Niijima A. SCN output drives the autonomic nervous system: with special reference to the autonomic function related to the regulation of glucose metabolism. Prog Brain Res 111: 253–272, 1996 [DOI] [PubMed] [Google Scholar]

[B160] 160. Nagai K, Nagai N, Sugahara K, Niijima A, Nakagawa H. Circadian rhythms and energy metabolism with special reference to the suprachiasmatic nucleus. Neurosci Biobehav Rev 18: 579–584, 1994 [DOI] [PubMed] [Google Scholar]

[B161] 161. Nakahata Y, Grimaldi B, Sahar S, Hirayama J, Sassone-Corsi P. Signaling to the circadian clock: plasticity by chromatin remodeling. Curr Opin Cell Biol 19: 230–237, 2007 [DOI] [PubMed] [Google Scholar]

[B162] 162. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P. The NAD^+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134: 329–340, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B163] 163. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD⁺ salvage pathway by CLOCK-SIRT1. Science 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B164] 164. Nakajima M, Imai K, Ito H, Nishiwaki T, Murayama Y, Iwasaki H, Oyama T, Kondo T. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308: 414–415, 2005 [DOI] [PubMed] [Google Scholar]

[B165] 165. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, Turek FW. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 20: 8138–8143, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B166] 166. O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320: 949–953, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B167] 167. O'Neill JS, Reddy AB. Circadian clocks in human red blood cells. Nature 469: 498–503, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B168] 168. O'Neill JS, van Ooijen G, Dixon LE, Troein C, Corellou F, Bouget FY, Reddy AB, Millar AJ. Circadian rhythms persist without transcription in a eukaryote. Nature 469: 554–558, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B169] 169. O'Reardon JP, Peshek A, Allison KC. Night eating syndrome: diagnosis, epidemiology and management. CNS Drugs 19: 997–1008, 2005 [DOI] [PubMed] [Google Scholar]

[B170] 170. O'Reardon JP, Ringel BL, Dinges DF, Allison KC, Rogers NL, Martino NS, Stunkard AJ. Circadian eating and sleeping patterns in the night eating syndrome. Obesity Res 12: 1789–1796, 2004 [DOI] [PubMed] [Google Scholar]

[B171] 171. O'Reardon JP, Stunkard AJ, Allison KC. Clinical trial of sertraline in the treatment of night eating syndrome. Int J Eating Disorders 35: 16–26, 2004 [DOI] [PubMed] [Google Scholar]

[B172] 172. Obrietan K, Impey S, Smith D, Athos J, Storm DR. Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274: 17748–17756, 1999 [DOI] [PubMed] [Google Scholar]

[B173] 173. Obrietan K, Impey S, Storm DR. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature Neurosci 1: 693–700, 1998 [DOI] [PubMed] [Google Scholar]

[B174] 174. Oishi K, Atsumi G, Sugiyama S, Kodomari I, Kasamatsu M, Machida K, Ishida N. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett 580: 127–130, 2006 [DOI] [PubMed] [Google Scholar]

[B175] 175. Okano S, Akashi M, Hayasaka K, Nakajima O. Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice. Neurosci Lett 451: 246–251, 2009 [DOI] [PubMed] [Google Scholar]

[B176] 176. Oster H, Damerow S, Hut RA, Eichele G. Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes. J Biol Rhythms 21: 350–361, 2006 [DOI] [PubMed] [Google Scholar]

[B177] 177. Oster H, Damerow S, Kiessling S, Jakubcakova V, Abraham D, Tian J, Hoffmann MW, Eichele G. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab 4: 163–173, 2006 [DOI] [PubMed] [Google Scholar]

[B178] 178. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3: 591–605, 2002 [DOI] [PubMed] [Google Scholar]

[B179] 179. Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab 12: 174–186, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B180] 180. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307–320, 2002 [DOI] [PubMed] [Google Scholar]

[B181] 181. Pandit R, de Jong JW, Vanderschuren LJ, Adan RA. Neurobiology of overeating and obesity: the role of melanocortins and beyond. Eur J Pharmacol 660: 28–42, 2011 [DOI] [PubMed] [Google Scholar]

[B182] 182. Parkes KR. Shift work and age as interactive predictors of body mass index among offshore workers. Scand J Work Environ Health 28: 64–71, 2002 [DOI] [PubMed] [Google Scholar]

[B183] 183. Pendergast JS, Nakamura W, Friday RC, Hatanaka F, Takumi T, Yamazaki S. Robust food anticipatory activity in BMAL1-deficient mice. PloS One 4: e4860, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B184] 184. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304: 110–115, 2004 [DOI] [PubMed] [Google Scholar]

[B185] 185. Pitts S, Perone E, Silver R. Food-entrained circadian rhythms are sustained in arrhythmic Clk/Clk mutant mice. Am J Physiol Regul Integ Comp Physiol 285: R57–R67, 2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B186] 186. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251–260, 2002 [DOI] [PubMed] [Google Scholar]

[B187] 187. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nature Struct Mol Biol 14: 1207–1213, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B188] 188. Ralph MR, Menaker M. A mutation of the circadian system in golden hamsters. Science 241: 1225–1227, 1988 [DOI] [PubMed] [Google Scholar]

[B189] 189. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai SI, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD⁺ biosynthesis. Science 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B190] 190. Reddy AB, Karp NA, Maywood ES, Sage EA, Deery M, O'Neill JS, Wong GK, Chesham J, Odell M, Lilley KS, Kyriacou CP, Hastings MH. Circadian orchestration of the hepatic proteome. Curr Biol 16: 1107–1115, 2006 [DOI] [PubMed] [Google Scholar]

[B191] 191. Reddy AB, Maywood ES, Karp NA, King VM, Inoue Y, Gonzalez FJ, Lilley KS, Kyriacou CP, Hastings MH. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology 45: 1478–1488, 2007 [DOI] [PubMed] [Google Scholar]

[B192] 192. Reilly T, Waterhouse J. Sports performance: is there evidence that the body clock plays a role? Eur J Appl Physiol 106: 321–332, 2009 [DOI] [PubMed] [Google Scholar]

[B193] 193. Reiter RJ, Tan DX, Korkmaz A, Ma S. Obesity and metabolic syndrome: association with chronodisruption, sleep deprivation, and melatonin suppression. Ann Med 2011 [DOI] [PubMed] [Google Scholar]

[B194] 194. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118, 2005 [DOI] [PubMed] [Google Scholar]

[B195] 195. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol 22: 939–943, 2012 [DOI] [PubMed] [Google Scholar]

[B196] 196. Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC, O'Hara BF. Role of melanopsin in circadian responses to light. Science 298: 2211–2213, 2002 [DOI] [PubMed] [Google Scholar]

[B197] 197. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2: e377, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B198] 198. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Jr, Vitiello MV, Zhdanova IV. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep 30: 1484–1501, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B199] 199. Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 54: 120–124, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B200] 200. Saifur Rohman M, Emoto N, Nonaka H, Okura R, Nishimura M, Yagita K, van der Horst GT, Matsuo M, Okamura H, Yokoyama M. Circadian clock genes directly regulate expression of the Na⁺/H⁺ exchanger NHE3 in the kidney. Kidney Int 67: 1410–1419, 2005 [DOI] [PubMed] [Google Scholar]

[B201] 201. Salgado-Delgado R, Angeles-Castellanos M, Buijs MR, Escobar C. Internal desynchronization in a model of night-work by forced activity in rats. Neuroscience 154: 922–931, 2008 [DOI] [PubMed] [Google Scholar]

[B202] 202. Scheer FA, Van Doornen LJ, Buijs RM. Light and diurnal cycle affect autonomic cardiac balance in human: possible role for the biological clock. Auton Neurosci 110: 44–48, 2004 [DOI] [PubMed] [Google Scholar]

[B203] 203. Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 43: 192–197, 2004 [DOI] [PubMed] [Google Scholar]

[B204] 204. Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell 111: 919–922, 2002 [DOI] [PubMed] [Google Scholar]

[B205] 205. Schlierf G, Dorow E. Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate-induction in man and their modification by nocturnal suppression of lipolysis. J Clin Invest 52: 732–740, 1973 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B206] 206. Schmutz I, Ripperger JA, Baeriswyl-Aebischer S, Albrecht U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev 24: 345–357, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B207] 207. Schwartz MD, Urbanski HF, Nunez AA, Smale L. Projections of the suprachiasmatic nucleus and ventral subparaventricular zone in the Nile grass rat (Arvicanthis niloticus). Brain Res 1367: 146–161, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B208] 208. Schwartz WJ, Reppert SM. Neural regulation of the circadian vasopressin rhythm in cerebrospinal fluid: a pre-eminent role for the suprachiasmatic nuclei. J Neurosci 5: 2771–2778, 1985 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B209] 209. Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci USA 103: 10224–10229, 2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B210] 210. Seaman GV, Engel R, Swank RL, Hissen W. Circadian periodicity in some physicochemical parameters of circulating blood. Nature 207: 833–835, 1965 [DOI] [PubMed] [Google Scholar]

[B211] 211. Shearman LP, Jin X, Lee C, Reppert SM, Weaver DR. Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol Cell Biol 20: 6269–6275, 2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B212] 212. Sheward WJ, Maywood ES, French KL, Horn JM, Hastings MH, Seckl JR, Holmes MC, Harmar AJ. Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice. J Neurosci 27: 4351–4358, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B213] 213. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12: 654–661, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B214] 214. Shimba S, Ishii N, Ohta Y, Ohno T, Watabe Y, Hayashi M, Wada T, Aoyagi T, Tezuka M. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA 102: 12071–12076, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B215] 215. Siepka SM, Yoo SH, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129: 1011–1023, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B216] 216. Sladek FM. What are nuclear receptor ligands? Mol Cell Endocrinol 334: 3–13, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B217] 217. Smith VM, Sterniczuk R, Phillips CI, Antle MC. Altered photic and non-photic phase shifts in 5-HT(1A) receptor knockout mice. Neuroscience 157: 513–523, 2008 [DOI] [PubMed] [Google Scholar]

[B218] 218. Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation 97: 2213–2221, 1998 [DOI] [PubMed] [Google Scholar]

[B219] 219. Sonoda J, Mehl IR, Chong LW, Nofsinger RR, Evans RM. PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 104: 5223–5228, 2007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B220] 220. Stanley BG, Leibowitz SF. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci 35: 2635–2642, 1984 [DOI] [PubMed] [Google Scholar]

[B221] 221. Stehle JH, Foulkes NS, Pevet P, Sassone-Corsi P. Developmental maturation of pineal gland function: synchronized CREM inducibility and adrenergic stimulation. Mol Endocrinol 9: 706–716, 1995 [DOI] [PubMed] [Google Scholar]

[B222] 222. Steinberger J, Daniels SR, Eckel RH, Hayman L, Lustig RH, McCrindle B, Mietus-Snyder ML. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 119: 628–647, 2009 [DOI] [PubMed] [Google Scholar]

[B223] 223. Stephan FK, Swann JM, Sisk CL. Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 25: 346–363, 1979 [DOI] [PubMed] [Google Scholar]

[B224] 224. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69: 1583–1586, 1972 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B225] 225. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science 291: 490–493, 2001 [DOI] [PubMed] [Google Scholar]

[B226] 226. Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ. Extensive and divergent circadian gene expression in liver and heart. Nature 417: 78–83, 2002 [DOI] [PubMed] [Google Scholar]

[B227] 227. Sujino M, Masumoto KH, Yamaguchi S, van der Horst GT, Okamura H, Inouye ST. Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of genetically arrhythmic mice. Curr Biol 13: 664–668, 2003 [DOI] [PubMed] [Google Scholar]

[B228] 228. Sutton GM, Perez-Tilve D, Nogueiras R, Fang J, Kim JK, Cone RD, Gimble JM, Tschop MH, Butler AA. The melanocortin-3 receptor is required for entrainment to meal intake. J Neurosci 28: 12946–12955, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B229] 229. Suwazono Y, Dochi M, Sakata K, Okubo Y, Oishi M, Tanaka K, Kobayashi E, Kido T, Nogawa K. A longitudinal study on the effect of shift work on weight gain in male Japanese workers. Obesity 16: 1887–1893, 2008 [DOI] [PubMed] [Google Scholar]

[B230] 230. Tain YL, Huang LT, Lin IC, Lau YT, Lin CY. Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats. J Pineal Res 49: 390–398, 2011 [DOI] [PubMed] [Google Scholar]

[B231] 231. Tanofsky-Kraff M, Yanovski SZ. Eating disorder or disordered eating? Non-normative eating patterns in obese individuals. Obesity Res 12: 1361–1366, 2004 [DOI] [PubMed] [Google Scholar]

[B232] 232. Trumper BG, Reschke K, Molling J. Circadian variation of insulin requirement in insulin dependent diabetes mellitus the relationship between circadian change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon during euglycemia. Hormone metab Res 27: 141–147, 1995 [DOI] [PubMed] [Google Scholar]

[B233] 233. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308: 1043–1045, 2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B234] 234. Van Amelsvoort LG, Schouten EG, Kok FJ. Duration of shiftwork related to body mass index and waist to hip ratio. Int J Obes Relat Metab Disord 23: 973–978, 1999 [DOI] [PubMed] [Google Scholar]

[B235] 235. Van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D, Hoeijmakers JH, Yasui A. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627–630, 1999 [DOI] [PubMed] [Google Scholar]

[B236] 236. Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264: 719–725, 1994 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B237] 237. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci USA 106: 21453–21458, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B238] 238. Vong L, Ye C, Yang Z, Choi B, Chua S, Jr, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71: 142–154, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B239] 239. Vujovic N, Davidson AJ, Menaker M. Sympathetic input modulates, but does not determine, phase of peripheral circadian oscillators. Am J Physiol Regul Integ Comp Physiol 295: R355–R360, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B240] 240. Wang J, Yin L, Lazar MA. The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. J Biol Chem 281: 33842–33848, 2006 [DOI] [PubMed] [Google Scholar]

[B241] 241. Welsh DK, Logothetis DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14: 697–706, 1995 [DOI] [PubMed] [Google Scholar]

[B242] 242. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86: 1930–1935, 2001 [DOI] [PubMed] [Google Scholar]

[B243] 243. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha. Genes Dev 23: 2201–2209, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B244] 244. Wu T, Ni Y, Dong Y, Xu J, Song X, Kato H, Fu Z. Regulation of circadian gene expression in the kidney by light and food cues in rats. Am J Physiol Regul Integ Comp Physiol 298: R635–R641, 2010 [DOI] [PubMed] [Google Scholar]

[B245] 245. Xie X, Rigor P, Baldi P. MotifMap: a human genome-wide map of candidate regulatory motif sites. Bioinformatics 25: 167–174, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B246] 246. Xu B, Kalra PS, Farmerie WG, Kalra SP. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, adipocyte leptin gene expression and secretion: effects of food restriction. Endocrinology 140: 2868–2875, 1999 [DOI] [PubMed] [Google Scholar]

[B247] 247. Xu X, Graeff R, Xie Q, Gamble KL, Mori T, Johnson CH. Comment on “The Arabidopsis circadian clock incorporates a cADPR-based feedback loop”. Science 326: 230, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B248] 248. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptacek LJ, Fu YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434: 640–644, 2005 [DOI] [PubMed] [Google Scholar]

[B249] 249. Yan J, Wang H, Liu Y, Shao C. Analysis of gene regulatory networks in the mammalian circadian rhythm. PLoS Computat Biol 4: e1000193, 2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B250] 250. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear receptor expression links the circadian clock to metabolism. Cell 126: 801–810, 2006 [DOI] [PubMed] [Google Scholar]

[B251] 251. Yang X, Lamia KA, Evans RM. Nuclear receptors, metabolism, the circadian clock. Cold Spring Harbor Symp Quant Biol 72: 387–394, 2007 [DOI] [PubMed] [Google Scholar]

[B252] 252. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA. Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318: 1786–1789, 2007 [DOI] [PubMed] [Google Scholar]

[B253] 253. Yin L, Wu N, Lazar MA. Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nuclear Receptor Signaling 8: e001, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B254] 254. Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, Menaker M, Takahashi JS. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101: 5339–5346, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B255] 255. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med 16: 1152–1156, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B256] 256. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432, 1994 [DOI] [PubMed] [Google Scholar]

[B257] 257. Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400: 169–173, 1999 [DOI] [PubMed] [Google Scholar]

[B258] 258. Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, Bonny O, Firsov D. Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci USA 106: 16523–16528, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B259] 259. Zulley J, Wever R, Aschoff J. The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature. Pflügers Arch 391: 314–318, 1981 [DOI] [PubMed] [Google Scholar]

PERMALINK

Metabolism and the Circadian Clock Converge

Kristin Eckel-Mahan

Paolo Sassone-Corsi

Abstract

I. INTRODUCTION

A. A Brief Overview of Circadian Physiology

Figure 1.

Table 1.

Figure 2.

B. Metabolic Homeostasis

II. SYSTEMS HOMEOSTASIS AND CIRCADIAN RHYTHMICITY OF PROCESSES INVOLVED IN ENERGY BALANCE

A. Feeding Is a Circadian Rhythm

B. Food as a Zeitgeber, a Metabolic Circadian Cue

C. Circadian Rhythmicity of Energy Expenditure

D. Malfunctioning Clocks and Metabolic Disease

III. CIRCADIAN RHYTHMS IN METABOLIC TISSUES

A. How the Brain Talks to the Periphery and Vice Versa

Figure 3.

B. Circadian Rhythmicity Within Metabolic Tissues

Figure 4.

1. Circadian rhythmicity in the brain

A) CIRCADIAN OSCILLATIONS IN NEURONS OF THE CENTRAL PACEMAKER.

B) CIRCADIAN OSCILLATIONS IN FOOD ENTRAINABLE ENSEMBLES OF THE BRAIN.

2. The hepatic circadian clock

Figure 5.

3. Circadian rhythmicity in metabolic peripheral tissues

C. Clock Gene Function Within Metabolic Tissues

Table 2.

Figure 6.

IV. MOLECULAR RHYTHMICITY OF METABOLITES AND THEIR REGULATORY ENZYMES

A. Rhythmicity in Metabolic Enzymes

1. Rhythms in enzyme expression

Figure 7.

2. Rhythms in enzymatic activity

B. Rhythmic Metabolite Production and Use

V. FROM METABOLITES TO PHYSIOLOGY

GRANTS

DISCLOSURES

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases