Metabolic Homeostasis: It’s All in the Timing

Abstract

Cross-talk between peripheral tissues is essential to ensure the coordination of nutrient intake with disposition during the feeding period, thereby preventing metabolic disease. This mini-review considers the interactions between the key peripheral tissues that constitute the metabolic clock, each of which is considered in a separate mini-review in this collation of articles published in Endocrinology in 2020 and 2021, by Martchenko et al (Circadian rhythms and the gastrointestinal tract: relationship to metabolism and gut hormones); Alvarez et al (The microbiome as a circadian coordinator of metabolism); Seshadri and Doucette (Circadian regulation of the pancreatic beta cell); McCommis et al (The importance of keeping time in the liver); Oosterman et al (The circadian clock, shift work, and tissue-specific insulin resistance); and Heyde et al (Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism). The use of positive- and negative-feedback signals, both hormonal and metabolic, between these tissues ensures that peripheral metabolic pathways are synchronized with the timing of food intake, thus optimizing nutrient disposition and preventing metabolic disease. Collectively, these articles highlight the critical role played by the circadian clock in maintaining metabolic homeostasis.

One of the underlying principles of metabolic homeostasis is the seamless transition between periods of nutrient availability and nutrient scarcity. In mammals, this is maintained through a careful balance between nutrient deposition during periods of feeding and stored nutrient liberation during fasting. Metabolic homeostasis is mediated at the level of several key peripheral organs including, most notably, the gastrointestinal tract to which ingested nutrients are first delivered and which itself houses another “organ”, the intestinal microbiome, the pancreatic islet cells that release metabolic hormones, and the nutrient depots liver, skeletal muscle, and adipocytes. The actions of all of these diverse organs must be temporally coordinated so as to limit, for example, dysglycemia due to hepatic glucose production or dyslipidemia due to enhanced lipolysis during periods of dietary nutrient absorption. In humans and, indeed, all mammals, metabolic homeostasis is determined at the level of the brain by the wake-sleep cycle. Mammals differ in their relationship between activity levels and the light-dark periods, with some species such as humans being active during the day, whereas others, including rodents, are active at night. However, the causal relationship between wakefulness and the ability to ingest nutrients is maintained across all species and is, in large part, determined by the circadian clock.

In this mini-review, the essential role of the circadian clock in ensuring metabolic homeostasis is discussed from the perspective of synchronization between the key peripheral metabolic tissues during the feeding period. More focused reviews of the circadian biology of each individual metabolic tissue have recently been published in Endocrinology as mini-reviews (1-6) and are collated within this special online collection.

The circadian clock is an integrated transcriptional-translational autoregulatory feedback loop that exists in all nucleated cells of the body, wherein activation of the core genes, ARNTL (aka brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 [BMAL1]) and CLOCK (circadian locomotor output cycles kaput), increases expression of the regulatory proteins, PERIOD (PER1-3) and CRYPTOCHROME (CRY1-2), which, in turn, feedback-inhibit BMAL1 and CLOCK. Degradation of PER and CRY then releases the positive arm of the clock for another cycle, with input from many other proteins, further fine-tuning these signals (Fig. 1). In mammals, the activating signal or zeitgeber (ZT) for the core clock is light, received through specialized cells in the retina and delivered to the suprachiasmatic nuclei via the retinohypothalamic tract (Fig. 2) (7-10).

Figure 1.

Schematic of the molecular clock. Expression of the core clock proteins, BMAL1 and CLOCK, stimulates the production of PERIOD (PER1-3) and CRYPTOCHROME (CRY1-2) which, in turn, feedback-inhibit BMAL1 and CLOCK. The period of transcriptional-translational autoregulatory feedback loop is determined by the rate of degradation of PER and CRY by casein kinase 1 (CK1) δ/ε and F-box and leucine-rich repeat protein 3 (FBXL3), respectively. This generates an anti-phasic rhythm in the positive and negative arms of the clock, as illustrated for BMAL1 and PER2 during the day (yellow) and night (gray) periods. Additional input into the core clock is provided by retinoic acid receptor-related orphan receptor (ROR) α/β/γ, nuclear receptor subfamily 1 group D (REV-ERB) α/β, albumin D-box binding protein (DBP) and nuclear factor, interleukin 3 regulated (NFIL3).

Figure 2.

Schematic of the metabolic clock. Light entrainment of the master clock in the suprachiasmatic nuclei determines the active/feeding and inactive/fasting periods. The main peripheral tissues in the metabolic clock are the gastrointestinal tract, with its resident microbiome, the pancreatic islets, the liver, the skeletal muscle and the adipocytes, all of which express cell-autonomous clocks that are synchronized to ensure metabolic homeostasis.

The importance of the circadian clock in metabolic homeostasis is emphasized by epidemiologic data showing increased risk for metabolic disruption or disease (ie, insulin resistance, dyslipidemia, obesity, impaired glucose tolerance, type 2 diabetes) in shift workers and those with jet lag or altered light exposure, as well as in rodents with mutations or knockout of specific clock genes (11-25). The critical role of the clock in metabolic homeostasis is further emphasized by findings that polymorphisms in the core clock genes are associated with alterations in the timing of food intake, as well as with obesity, hyperglycemia, and diabetes (22, 26-30). It has also been reported that weight loss is more difficult in humans who routinely eat late in the day (31). Studies in rodent models have further demonstrated that high-fat feeding not only induces obesity, but also disrupts the normal pattern of food intake in rodents (32), creating a vicious cycle of perturbed metabolic homeostasis. As a consequence, obesogenic (high-fat) diets (HFDs) are commonly used as a model of circadian disruption.

The core clock in the suprachiasmatic nuclei plays an integral role in peripheral metabolism through the regulation of food intake as well as of the diurnal patterns in several metabolic hormones (eg, cortisol and growth hormone). However, it has become increasingly clear over the past few decades that peripheral tissues themselves are also regulated at the molecular level by the core clock machinery. Indeed, in a survey of multiple tissues in mice, 43% of all genes were found to exhibit circadian rhythmicity in one or more tissues (33). These effects are mediated through direct actions of the clock proteins on target genes (approximately 10% to 20% of all genes (34, 35)) or indirectly, such as through epigenetic modulation of chromatin accessibility to transcription factors or as downstream effects of the clock-controlled genes (33, 36-38). However, central to the notion of the peripheral clock is the integration of these clocks between the metabolic tissues. Hence, although these tissues all express cell-autonomous clocks, they also work in a synchrony with other peripheral tissues, through both feedforward and feedback crosstalk, to maintain metabolic homeostasis during the feeding and fasting periods. Beginning with the gut and proceeding through the islet to the storage tissues (ie, liver, muscle, adipose), this review article considers the signals that are initiated by food intake, as well as those that function to terminate these temporally synchronized responses.

Feedforward Synchronization of Metabolic Responses to Food Intake

The intestinal epithelial cells (IECs) are the first point of contact of ingested nutrients with a metabolic tissue, playing a critical role in the digestion of macromolecules and absorption of the digestive products. As reviewed by Martchenko et al (1), the IECs not only express the core clock machinery, but demonstrate multiple, synchronized circadian rhythms, many of which are coordinated by nutrient intake (39). For example, crypt cell proliferation increases before the active/feeding period in rodents (40), which permits anticipatory growth of the villus to enhance the handling of nutrients (41). The genes for several IEC brush border enzymes and nutrient as well as mineral transporter/handling proteins also exhibit circadian rhythms, increasing in association with the feeding period to enhance digestive and absorptive capacity (42-46). Furthermore, genetic disruption of the circadian clock is associated with abnormal patterns of carbohydrate, fat, and protein absorption from the gut (47). While some of these genes appear to be under the direct regulatory control of the clock proteins, circadian vagal input to the gut may also affect their expression (48, 49), and even shifting the timing of nutrient intake can induce a parallel shift in their expression (44). It has also become clear in recent years that the gut microbiome plays a role in entraining these patterns of gene expression (50, 51), as reviewed by Alvarez et al (2). These changes are mediated, at least in part, through recruitment of histone deacetylase 3 to the IEC chromatin, as well as by the transcription factor, nuclear factor-interleukin-3-regulated, resulting in rhythmic changes in the expression of genes involved in IEC nutrient handling (46, 52). Whether specific microbial metabolites are implicated in these changes is not well defined, but has been suggested to include both short-chain fatty acids (SCFAs; eg, butyrate) and inositol-1,4,5-trisphosphate, which exhibit circadian patterns of expression linked to timing of nutrient ingestion (53-56). As a consequence, total absence of the microbiome in germ-free mice induces changes in the patterns of nutrient absorption (52). Consistent with these findings, transfer of the fecal microbiome from jet-lagged mice to germ-free animals induces metabolic disease, whereas microbial depletion prevents metabolic disruption in jet-lagged mice (57).

In addition to the absorptive enterocytes, the enteroendocrine cells also exhibit circadian patterns. In male rats, the circadian rhythms in cholecystokinin (from I cells), glucose-dependent insulinotrophic polypeptide (GIP; from K cells) and neurotensin (from N cells) are positively correlated with the timing of food intake and nutrient handling capacity (58-61), whereas the peak of ghrelin (from X/A cells) occurs during the fasting/inactive period (62). Nevertheless, whether the cells that secrete these gut hormones demonstrate cell-autonomous clock genes remains largely unknown. However, recent studies have clearly demonstrated that clock genes, as well as the intestinal microbiome, are required for the circadian rhythm in intestinal L-cell function. The L-cell cosecretes multiple endocrine hormones derived from the same prohormone (GCG), including the incretin and satiety factor glucagon-like peptide-1 (GLP-1) (63-65), the intestinotrophic hormone GLP-2 (66), and the anorexigen oxyntomodulin (67), and circadian rhythms that peak at the onset of the active/feeding period have been demonstrated for GLP-1 in rodents and humans (40, 60, 68-70). Importantly, the rhythm of GLP-2 secretion, which is presumed to parallel that of the cosecreted GLP-1, may assist in coordinating the pattern of nutrient absorption, as GLP-2 stimulates translocation of sodium glucose transporter-1 to the enterocyte brush border membrane (71). Furthermore, both GIP and GLP-2 enhance glucose-transporter-2 insertion into the basolateral membrane, thereby increasing glucose absorption across the gut epithelium (72), while GIP additionally serves as an incretin hormone (73). Finally, the intestinal L cell secretes one additional satiety factor, peptide YY (74), which is also released at the highest levels during the active period in rats (75).

The normal rhythm in L-cell secretion follows the pattern in food intake, suggesting that nutrient ingestion is a zeitgeber for the intestinal L cell (40). HFDs as well as the saturated fatty acid palmitate also disrupt the L-cell clock through suppression of Arntl (60, 76, 77). Furthermore, whole-body as well as L-cell Arntl knockout results in impaired rhythmic L-cell secretion (70, 78). However, intestinal dysbiosis, including that induced by alterations in the timing of feeding, in dietary composition (eg, a high-fat or Western, high-fat/high-sucrose diet) and antibiotic administration, as well as its total absence in germ-free mice is also associated with a profound disruption in the rhythm of L-cell secretion, and transfer of a normal microbiome into germ-free mice restores their L-cell secretory pattern (40, 60, 76). Although L-cell hormone secretion is known to be stimulated both by SCFAs and microbial-derived secondary bile acids (79, 80), whether and how these or other microbial metabolites may entrain the L-cell clock machinery remains unknown. However, numerous studies have implicated the species Akkermansia muciniphila in microbiome-induced GLP-1 secretion and associated improvements in metabolic control, with recent studies indicating a role for an integral membrane protein in these effects (60, 81-84).

Following nutrient digestion and absorption, the next key player in the metabolic clock is the pancreatic islet. As reviewed by Seshadri and Doucette (3), humans exhibit increased insulin secretion at the onset of the normal feeding period. Altered circadian release of insulin and expression of the islet clock genes have also been demonstrated in type 2 diabetes (85-88). However, it is important to recognize that changes in insulin sensitivity also affect β-cell function in vivo (89). Hence, more direct demonstrations of a role for the islet circadian clocks have been shown through targeted disruptions in the core clock machinery, with β-cell clock-deficient mice exhibiting impaired rhythmic insulin secretion and metabolic disease (90, 91). At the islet and single-cell level, both β- and α-cells have also been demonstrated to exhibit cell-autonomous circadian clocks, with the peak activities of these 2 cell types temporally offset, presumably to allow for increased release of insulin during feeding and of glucagon during fasting, respectively (18, 87, 90, 92-94). Consistent with studies showing circadian patterns in insulin secretion, the cosecretion of islet amyloid polypeptide (or amylin) is also likely to be circadian, and may contribute to rhythmic changes not only in insulin secretion but also in downstream insulin sensitivity (95-97).

Interestingly, consistent with findings of circadian rhythms in insulin release in response to oral but not intravenous glucose (98), increasing the levels of the incretin hormones GLP-1 and GIP at the onset of the normal feeding/active period in rats further enhances the insulin secretory response to glucose as compared to that found under the same conditions during the normal fasting/inactive period; in mice, this pattern is reversed, likely due to associated rhythms in insulin sensitivity (40, 60). As a result, the circadian rhythms in GLP-1 and GIP appear both to coordinate and further increase the β-cell response to nutrient ingestion, with optimal effectiveness being observed during the normal feeding period. GLP-1 has also been reported to synchronize the β cell clock in vitro through a signaling pathway that likely involves activation of cyclic adenosine monophosphate (99). Circadian patterns in downstream signaling pathways, but not in the GLP-1 receptor, have also been reported for the β cell (90). Furthermore, the pattern in GLP-1 secretion may also affect the rhythm in glucagon release through its known inhibitory effects on the α cell (100). Finally, the intestinal microbiome has also been implicated in directly regulating islet β-cell function, most notably through the SCFA receptors FFA2 and FFA3 (101). It can therefore be presumed, although not shown to date, that the circadian patterns in microbial metabolites may also play a role as a β-cell zeitgeber, contributing to the normal rhythm of insulin secretion. Also, similar to findings in the intestinal enterocytes and L cells, HFDs and high-glucose/palmitate have been shown to disrupt islet clock gene expression (86, 91, 94, 102). Arntl is also required for the normal β-cell adaptive response to an HFD (91, 103), and light-induced circadian disruption and an HFD have been reported to synergistically impair β-cell function (93).

In addition to the well-established anabolic effects of insulin on the liver, skeletal muscle, and adipose tissue, all of these different cell types are also known to express cell-autonomous circadian clocks, as reviewed by McCommis and Butler (4), Oosterman et al. (5), and Heyde and colleagues (6), respectively.

Within the hepatocytes, vital processes such as glucose and fatty acid uptake are stimulated by insulin, whereas gluconeogenesis and lipolysis are upregulated by glucagon, among other catabolic hormones that also demonstrate circadian rhythms (eg, growth hormone and cortisol). However, as reviewed by McCommis and Butler (4), hepatic nutrient handling is also temporally controlled by the circadian clock machinery. Hepatic insulin sensitivity, which is normally increased during the feeding/active period in humans, is reduced in patients with type 2 diabetes (104). Furthermore, clock gene knockout mice and mice fed exclusively during the normal fasting/light period display a loss in rhythmicity of both the clock and metabolic genes in the liver, resulting in inappropriate gluconeogenesis and glucose uptake, hepatic steatosis, and abnormal plasma glucose, free fatty acid, and triglyceride levels (16, 105-108). At the molecular level, the expression of hepatic metabolic genes, including glucose transporter-2, glycogen synthase and phosphorylase, peroxisome proliferator-activated receptor α, and sterol regulatory element-binding protein-1, is controlled by the circadian clock, resulting in rhythms that are coordinated appropriately with the feeding and fasting states (108-110). Curiously, however, alterations in the timing of food intake can also entrain nutrient-specific gene expression in the liver independent of the circadian clock (111). These findings suggest that the rhythm in hepatic nutrient handling is entrained by nutrients delivered through the portal circulation, as well as by the associated rhythm in insulin which is an important zeitgeber for the induction of PERIOD (112-114). Furthermore, the hormones oxyntomodulin and ghrelin have also been shown to serve as a direct link between the gut and circadian rhythms in the liver, most notably through the modulation of Per2 expression (115, 116). SCFAs have also been shown to entrain the hepatic clock, which may further serve to synchronize the hepatic circadian rhythms with nutrient intake (117-119).

The liver clock is disrupted by feeding of an HFD, resulting in insulin resistance and a reprogramming of the hepatic transcriptome and downstream metabolome. Similarly, administration of nonobesogenic doses of the saturated fatty acid palmitate in vivo disrupts hepatic circadian rhythmicity and impairs recruitment of BMAL1 to its target genes (120-122). Direct exposure of hepatocytes to palmitate also results in disrupted clock gene expression and cellular function through destabilization of the BMAL1/CLOCK heterodimer (122, 123).

Skeletal muscle is the main tissue responsible for insulin-mediated glucose uptake, and insulin resistance in this tissue is therefore a key contributor to impaired glucose tolerance as well as type 2 diabetes (124). Glucose transporter-4 translocation to the plasma membrane is a key function of insulin in myocytes, and glucose uptake is thereby synchronized with food intake through the circadian pattern in insulin secretion. However, skeletal muscle functions are also regulated by a cell-autonomous clock, as reviewed by Oosterman et al (5). Rhythmic expression of the clock regulates the gene for glucose transporter-4 (125), and may contribute to the known rhythms in both mitochondrial respiratory capacity and myokine secretion (126, 127). Indeed, muscle-specific Arntl knockout results in insulin resistance, as characterized by impaired insulin-dependent glucose uptake (125). Furthermore, the master regulator of skeletal muscle biogenesis, myoblast-determination protein-1, is also a direct target of the circadian clock (128).

The importance of the circadian clock to muscle function has largely been determined using high-fat fed rodent models that, as in the liver, exhibit impaired BMAL1 recruitment to target genes, resulting in dysregulation of approximately 40% of the diurnal metabolome (120). These effects of obesogenic feeding were also associated with reduced insulin action and mitochondrial oxidative phosphorylation within skeletal muscle (129, 130). Conversely, muscle-specific Arntl knockout mice on an HFD were found to have increased skeletal muscle oxidative capacity and reduced obesity (125). Alterations in the timing of food intake also disrupt clock gene expression in the skeletal muscle in association with markers of insulin resistance, while treatment of myotubes with palmitate downregulates BMAL1/CLOCK (106, 129-131). Finally, although limited work has been conducted in humans, one study using obese insulin-resistant volunteers given identical doses of saturated-, monounsaturated- or polyunsaturated fatty acids showed a more profound deleterious effect of the saturated fat on the skeletal muscle clock gene (132). Collectively, therefore, it appears that the timing of nutrient ingestion may contribute to the synchronization of skeletal muscle function within the metabolic clock (107). In contrast, at least one study has suggested that the associated patterns in insulin release do not serve as an important zeitgeber for skeletal muscle (113).

The other 2 major effectors of the metabolic clock are the white and brown adipose tissue, which are essential for energy storage (WAT) and nonshivering thermogenesis (BAT), respectively. The circadian clock genes expressed by WAT have been shown to regulate lipid metabolism, with the genes for key transporters and metabolic enzymes all exhibiting circadian rhythmicity under the direct control of BMAL1 (as reviewed by Heyde et al) (6). WAT functions are also affected by the hormones insulin and glucagon and thus possibly by their circadian rhythms. Furthermore, the rhythms in nutrient influx on feeding, such as those in free fatty acids, also contribute to the circadian activity of the WAT (133). Consistent with these findings, adipose-specific Arntl knockout mice have alterations in their diurnal gene expression profile, leading to altered fatty acid release into the bloodstream, whereas Arntl overexpression increases lipogenic gene expression in the WAT (134). Similarly, Clock-mutant animals have decreased lipolytic gene expression, with loss of the normal rhythms in circulating fatty acids, and obesity (135).

Exposure to HFD-feeding has been shown to dampen the amplitude in the circadian expression of the core molecular clock in WAT, thereby disrupting downstream targets including nuclear receptors as well as lipid metabolism pathways and leading to abnormal patterns in the release of fatty acids into the circulation (32). Interestingly, the clock disruption as induced by high-fat feeding is also associated with increased macrophage infiltration into the WAT and elevated expression of proinflammatory cytokines (136). Finally, palm oil administration to mice as well as palmitate treatment of adipocytes disrupts the circadian rhythms in association with increased adipogenic and reduced mitochondrial function markers (137). On the other hand, treatment with oleate, a monounsaturated fatty acid, largely opposes these effects, supporting the well-established health benefits of this fatty acid (137).

BAT tissue clock gene expression is negatively affected by high-fat feeding, with a decreased amplitude in cycling of the core clock components as well as decreased expression of uncoupling protein-1, the latter of which is also effected by circadian disruption (138). However, WAT also secretes a number of adipokines that affect BAT function, including the anorexigenic hormone leptin and the insulin sensitizer adiponectin, both of which oscillate with a circadian rhythm (139). Hence, not only is leptin expression stimulated by insulin, but it is also a direct target of the circadian clock machinery (140). Hence, adipose-specific deletion of Arntl results in alterations in the timing of leptin release and increases daytime feeding, leading to obesity (134). Importantly, leptin also increases uncoupling protein-1 expression in BAT, thereby increasing energy expenditure (141). Conversely, WAT release of adiponectin inhibits uncoupling protein-1 expression in BAT (142). The balance between leptin and adiponectin, therefore, with leptin positively and adiponectin inversely correlated to fat mass (143), contributes to overall metabolic homeostasis through the 24-hour day/night cycle. Finally, BAT activity is also affected by bile acids as well as several gut hormones with circadian rhythms, including cholecystokinin, which stimulates BAT through the sympathetic nervous system, and ghrelin, which inhibits BAT (144, 145). These factors thus serve to further coordinate circadian BAT activity with the feeding-fasting cycle.

It must be recognized that not all metabolic pathways, cells, and tissues are regulated by the circadian clock (33), as food-entrainable oscillations have been shown to exist in the absence of the circadian clock (146, 147). However, the mechanisms regulating such clock-independent rhythms have proven difficult to study. Nevertheless, the synchronization of metabolic functions between the key peripheral tissues has been established to be determined not only by the expression of cell-autonomous clock genes, but also by feedforward pathways that synchronize clock activity between these tissues. Disruptions in the circadian rhythms of one or more of these tissues, as can be induced by alterations in the dietary composition, the timing of nutrient intake, and/or in the microbiome, are therefore all associated with metabolic disease.

Feedback Coordination of Metabolic Responses to Food Intake

The main body of this review has covered some of the key mechanisms by which the temporal control of nutrient ingestion and subsequent disposition is tightly coordinated in a feedforward fashion. However, feedback loops between these circadian-regulated tissues also contribute to metabolic homeostasis. For example, nutrient ingestion stimulates the release of L-cell hormones that serve as short-term satiety factors (eg, GLP-1, oxyntomodulin, and peptide YY), whereas levels of the orexigen ghrelin and of the hyperglycemic hormone glucagon decrease with feeding; GLP-1 and peptide YY also serve as ileal brakes, slowing down the rate of nutrient digestion and absorption (148). Interleukin-6 secreted by skeletal muscle during exercise, and leptin released by WAT, both stimulate L-cell secretion (149, 150), while leptin also provides an orexigenic signal directly to the brain to suppress long-term food intake (151).

Chronotherapeutic Approaches to Treat Metabolic Disease

Chronotherapy is used extensively in the clinic, with many drugs given in a temporal fashion so as to maximize their effectiveness (33, 37). Given the extensive evidence linking circadian disruption to metabolic disease, the possible utility of chronotherapy for prevention and/or treatment has therefore become of increasing interest (152, 153). For example, the polyphenol resveratrol reverses the suppression of hepatic Arntl expression and induction of insulin resistance caused by keeping mice in constant darkness, as well as reversing the effects of high-fat feeding or palmitate on clock gene expression in the liver, WAT, and skeletal muscle (129, 154, 155). Similarly, the flavonoid nobiletin enhances insulin secretion through an Arntl-dependent mechanism, reduces hypercholesterolemia, and improves both circadian oscillations and mitochondrial function in skeletal muscle, thereby reversing the negative effects of obesogenic feeding (85, 103, 156). However, given recent studies demonstrating that humans are increasingly consuming food during the normal, fasting/inactive period (157), interest has also focused on the possible clinical benefits of “time-restricted feeding.” Indeed, there are now several reports of improved metabolism in humans who restrict their food intake to the daylight hours (158-161). However, whether such an approach is feasible in the “real world” will require additional long-term studies (162).

Conclusion

The importance of the circadian clock to normal physiology is becoming increasingly well recognized. As reviewed by experts in the field, this collection of articles published in Endocrinology also demonstrates the essential role of the peripheral clock in maintaining metabolic homeostasis, as evidenced not only by the highly synchronized interplay between the gut and its microbiome, pancreatic islet cells, hepatocytes, myocytes, and adipocytes, but by the metabolic consequences of circadian disruption in one or more of these different tissues.

Glossary

Abbreviations

BAT

brown adipose tissue

BMAL1

brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1

CLOCK

circadian locomotor output cycles kaput

CRY

cryptochrome

GIP

glucose-dependent insulinotrophic polypeptide

GLP-1

glucagon-like peptide-1

HFD

high-fat diet

IEC

intestinal epithelial cell

PER

period

SCFAs

short-chain fatty acids

WAT

white adipose tissue

Additional Information

Disclosures: The authors have nothing to disclose.

Data Availability

No new data were created or analyzed in this review article. Therefore, data sharing is not applicable.