Circadian-Mediated Regulation of Cardiometabolic Disorders and Aging with Time-Restricted Feeding

Abstract

Circadian rhythms are present throughout biology from the molecular level to complex behaviors like eating and sleeping. They are driven by molecular clocks within cells and different tissues can have unique rhythms. Circadian disruption can trigger obesity and other common metabolic disorders like aging, diabetes and cardiovascular disease, and circadian genes control metabolism. At an organismal level, feeding and fasting rhythms are key drivers of circadian rhythms. This underscores the bidirectional relationship between metabolism and circadian rhythms, and many metabolic disorders have circadian disruption or misalignment. Thus, studying circadian rhythms may offer new avenues for understanding the etiology and management of obesity. This review describes how circadian rhythm dysregulation is linked with cardiometabolic disorders, and how the lifestyle intervention of time-restricted feeding (TRF) regulates them. TRF reinforces feeding-fasting rhythms without reducing caloric intake and ameliorates metabolic disorders like obesity and associated cardiac dysfunction, along with reducing inflammation. TRF optimizes the expression of genes and pathways related to normal metabolic function, linking metabolism with TRF’s benefits and demonstrating the molecular link between metabolic disorders and circadian rhythms. TRF thus has tremendous therapeutic potential that could be easily adopted to reduce obesity-linked dysfunction and cardiometabolic disorders.

Introduction

Circadian rhythms are intrinsically driven daily rhythms that are highly conserved across biological systems and are critical in health and disease. They are particularly important in healthy metabolism and cardiac function, while they can become disrupted during aging. Circadian rhythms are also disrupted in many diseases and aligning rhythms with external daily cues could be beneficial, especially for cardiometabolic disorders. One approach to promote and align circadian and metabolic rhythms is time-restricted feeding and eating (TRF/TRE), where food is only consumed during an animal or person’s active phase. Here, we review circadian rhythms, TRF/TRE, and how they could be beneficial in cardiometabolic disorders, immune function, and obesity.

Circadian Rhythms and Time-Restricted Feeding and Eating

Circadian rhythms, metabolism, and obesity

Almost all organisms, from single-celled bacteria to humans, have an internally driven rhythm with a period of approximately 24 hours. This intrinsic timekeeping system is called the circadian clock (in Latin, circa means ‘about’ and diem means ‘day’). Every mature mammalian cell has rhythms that can be entrained by zeitgebers (‘time givers’) like light, other external stimuli like eating and physical activity, or endogenous signaling. Circadian clocks are cell-autonomous, self-sustaining, and have multiple rhythmic transcriptional/translational feedback loops¹. The highest resolution time-series transcriptomics study in primates was completed by Mure, et al. in baboons, with samples from 64 tissues collected every two hours throughout the day². In that study, approximately 80% of the genome had rhythmic expression, with the brain being overrepresented. This is consistent with results from our lab that in Drosophila, many transcripts in the head, periphery, and heart are rhythmic, demonstrating that this rhythmicity extends beyond mammals³. The majority of cycling transcripts in primates are ubiquitously-expressed genes, as opposed to tissue-specific genes, and genes involved in energy metabolism².

The suprachiasmatic nucleus (SCN) in the mammal brain is the pacemaker and master clock of the body, in addition to regulating peripheral clocks present in peripheral organs⁴. The SCN is situated in the ventral hypothalamus, directly above the optic chiasm. It receives input from specialized retinal ganglion cells (photosensitive retinal ganglion cells or melanopsin-containing retinal ganglion cells) in the eyes that detect ambient light and signal to the SCN through the retinohypothalamic tract³. The SCN then signals to peripheral tissues to regulate their peripheral clocks, alongside input from proximal signals like feeding behavior, autonomic signaling, and hormonal signals^5,6.

At a molecular level, circadian clocks consist of autoregulatory transcriptional feedback loops involving positive transcription factors like CLOCK (circadian locomotor output cycles kaput) or NPAS2 (Neuronal PAS domain protein 2), BMAL1 (brain and muscle ARNT-like 1) and ROR (retinoic acid receptor-related orphan receptor), and transcriptional repressors like CRY (cryptochrome), PER (period), and REV-ERB (nuclear receptor 1D1/2, NR1D1/2)⁷. CLOCK and BMAL1 heterodimerize and bind to E-box motifs of various target genes like Per1, Per2, Per3, Cry1, Cry2, NR1D1 (Rev-Erbα), and RORa, leading to their transcription. As the protein levels of CRY and PER increase, they form heterodimers and auto-inhibit their own transcription. As transcription of CRY and PER decreases and protein levels are degraded by the ubiquitin ligase complexes β-TrCP1 and FBXL3, this auto-inhibition is removed, increasing transcription and restarting the cycle. Additionally, there are many other negative/positive feedback loops beyond this core loop that help control the precision and magnitude of circadian rhythms^8–10. While clock gene expression is ubiquitous, different tissues in the body can have specific clock gene activity, circadian regulation, and zeitgebers, and the alignment of body clocks with each other and the environment external stimuli in the daily cycle is important for the body to function optimally. In fact, circadian misalignment may lead to the onset of pathological conditions in disease¹¹.

One condition that commonly leads to circadian misalignment and rhythm dampening is aging. At a cellular level, coordination of SCN neurons becomes impaired and expression of important coupling factors like vasopressin and GABA decrease with age¹². This loss of synchrony between neurons in the SCN weakens the central clock and can lead to dysregulation of peripheral circadian clocks, including in brain regions outside of the SCN¹², which can further result in altered amplitude and phase of peripheral rhythms characteristic of aging. Beyond aging, circadian rhythm dysfunction is seen in many common disorders like obesity, cardiovascular disease, and diabetes¹³. As aging is a significant risk factor for these diseases, it is important to study how aging-associated circadian disruption and aging-independent circadian disruption contribute to them and understand the mechanisms underlying their circadian disruptions. Additionally, since circadian rhythm disruption contributes to these diseases, it is possible that promoting circadian rhythms amplitude and alignment could be beneficial in these diseases.

Many diseases with circadian dysfunction can be considered metabolic disorders¹⁴. Metabolic disorders are any condition that disrupts normal body metabolism and prevents cells from performing essential biochemical functions in metabolism. They may be acquired from social determinants of health combined with genetic predisposition (like obesity, cardiovascular disease, type II diabetes, sporadic Alzheimer’s disease, and certain cancers) or be inherited (like phenylketonuria, albinism, some gout, and thyroid disease). Even aging can be considered a metabolic disorder, as metabolic activity is perturbed with age and rhythms are disrupted¹⁵. One impact of disturbing circadian rhythms can be disrupted metabolism and obesity-linked diseases such as type II diabetes and cardiovascular disease¹⁶. Any disruption in light exposure, eating rhythms, or sleep schedule can lead to obesity-associated dysfunction along with increased risk of these diseases¹⁶. Thus, interventions that optimize and align circadian rhythms throughout the body could be therapeutically relevant to a diverse set of metabolic disorders, including obesity. This is especially relevant for the subset of metabolic disorders that also present with cardiac dysfunction, which we refer to as cardiometabolic disorders.

Circadian rhythms and metabolic homeostasis in peripheral tissues

Emerging studies demonstrate that peripheral clocks are synchronized with the master clock in the SCN. Food intake is a strong zeitgeber that controls peripheral circadian clocks in metabolic organs, which contribute to the whole body’s clock¹⁷. Key peripheral clocks are involved in metabolism, and many rhythmic genes have substantial roles in various metabolic and biosynthetic processes such as glycolysis and gluconeogenesis, lipid and cholesterol metabolism, and oxidative phosphorylation pathways^18,19. Additionally, the rate-limiting steps in these various pathways are under circadian control²⁰. One note is that rhythmicity of various genes is variable in different tissues, so each tissue controls rhythmic gene expression to produce a unique signature in that tissue^3,21. Additionally, there can be tissue-specific exogenous zeitgebers that can influence rhythmicity, like the effect of food consumption on microbiome causing host metabolic gene changes²².

In anabolic and catabolic metabolism, processes are controlled by endogenous circadian clocks alongside external stimuli like feeding-fasting pattern, and can be controlled by metabolite concentration, endocrine signaling, and the microbiome²³. Clock mutant mice have altered metabolite expression that can becomes rhythmic again by enforcing scheduled feeding-fasting cycle²³. In the endocrine system, sensitivity to and production of many hormones like insulin, glucagon, cortisol, and catecholamines (epinephrine and norepinephrine), are influenced by circadian and peripheral clocks. Bmal1 knockout in the pancreas leads to disturbed glucose levels and insulin release despite having normal activity and feeding-fasting rhythms²⁴, which supports its circadian regulation. Additionally, sirtuins, a family of NAD⁺-dependent histone and protein deacetylases, influence lifespan by regulating energy metabolism and genome integrity, linking circadian rhythms and metabolism²⁵. SIRT1 influences clock-controlled role in insulin sensitivity and metabolism by regulating NAMPT expression and NAD availability²⁶. The clock-mediated oscillations in NAD control the activation of SIRT6 and SIRT3, modulating mitochondria activity and biogenesis and regulating metabolism, aging and lifespan²⁷. Cortisol, a steroidal hormone which is involved in metabolism and stress response, is influenced by the SCN²⁸. Cortisol’s production and secretion is controlled by the hypothalamic-pituitary axis and the autonomic nervous system. Both pathways are regulated by SCN through the paraventricular nucleus and upstream in the dorsal medial hypothalamus and the subparaventricular zone. Finally, the gut microbiome is critical for proper metabolism and has circadian rhythms that are implicated in obesity and metabolic disorders²². Thus, circadian rhythms are intricately linked to metabolic function, especially in peripheral clocks.

Circadian rhythms and the cardiovascular system

One key biological process influenced by circadian rhythms is the cardiovascular system, where cardiomyocyte function and blood flow to the atrium, ventricle, and aorta are circadian^29–31. In one study, gene expression of mice aortae was assessed and circadian rhythmicity was found there along with SCN and other peripheral organs. Many genes relevant to glucose and lipid metabolism, adipocyte maturation, protein folding, protein degradation, vascular integrity, and injury response have circadian oscillation²⁹. In healthy people, blood pressure, heart rate, and cardiac outputs are rhythmic as they decrease while sleeping and increase upon awakening^32,33. These parameters follow bimodal pattern with two acrophases, or peaks, (around 10am and 8pm) and two nadirs, or valleys, (around 3pm and 3am)³². These time-of-day fluctuations exist even in constant environmental and behavioral conditions, demonstrating that they are circadian in nature rather than diurnal³¹. Similarly, frequency of cardiovascular complications like myocardial infarction and stroke increases in the morning hours^34,35. The sympathetic nervous system increases signaling during those hours, which could result in increased pressure, viscosity, and coagulation of blood, as well as increasing the probability of thrombosis and infarction³⁶. Significantly, major cardiac dysfunction like myocardial infarction, cardiac death, and ischemic and hemorrhagic stroke also undergoes diurnal variation, peaking in early morning hours^37,38.

Time-restricted feeding and eating

Time-restricted feeding and eating are a behavioral intervention that promotes circadian alignment by emphasizing the importance of ‘when’ one eats food³⁹. TRF/TRE is a regimen in which food availability is restricted to active phase of organism and for certain hours of day, usually approximately 8–12 hours, without caloric restriction. This contrasts with ad libitum feeding (ALF) where food is always available for the animal to consume, which is normally used in animal studies. Typically, TRF is used to denote an experimental protocol used in animal studies where food is only provided for a set time, while TRE describes the human intervention. Timing TRF so food is consumed during the active phase (day for humans and Drosophila, night for rodents) of the light-dark cycle may positively impact body metabolism. Alternatively, inconsistent eating patterns and eating for a prolonged period like ALF and obesity can dampen circadian rhythms in the body, which are further deteriorated with aging. This maintenance of consistent feeding-fasting cycle can promote robust circadian rhythms⁴⁰.

TRF is beneficial in many models of metabolic disorders, especially obesity. Specifically, TRF reduces obesity-induced muscle and metabolic dysfunction, sarcomere disorganization, mitochondrial abnormalities, lipid infiltration and insulin resistance¹⁶. In both mice and Drosophila, TRF increases lean body mass and reduces body weight^16,41. In obese mice fed with a high-fat diet, TRF improves motor coordination, nutrient utilization and energy expenditure^41,42. These findings are replicated in Drosophila, where obese flies with TRF perform better in flight and geotaxis muscle function assays compared to ALF flies¹⁶. TRF is also beneficial in middle-aged flies, as it prevents age-dependent body-weight gain and leads to better consolidated night-time sleep³¹. This extends to other aging-related dysfunction, as TRF prevents age-associated cognitive decline in rats⁴³. Obesity and weight are risk factors for other cardiometabolic and age-associated diseases and TRF ameliorates both along with improving circadian rhythmicity, highlighting its broad therapeutic potential for cardiometabolic diseases.

One important debate in studying TRF/TRE is whether the beneficial effects are due to timing of eating, or solely due to caloric restriction because of the unavailability of food throughout the day. This is especially salient as caloric restriction is a well-studied approach to improve health and slow aging. One critical new TRE study reported that TRE did not lead to significantly more weight loss than caloric restriction alone in people with obesity⁴⁴. Both were beneficial for weight loss, blood pressure, and metabolic risk factors. It will be important to repeat these results alongside studying other metabolic (i.e. lipid metabolism, insulin resistance) or rhythmic changes between these groups, and to see whether these results generalize to people without obesity. While both TRE and caloric restriction are beneficial, there is compelling evidence that both have independent effects and there are two independent lines of evidence that support that the beneficial effects of TRF/TRE are unique and separate from beneficial effects of caloric restriction. First, TRF does not require caloric restriction to be beneficial. In animal models, TRF increases lifespan and prevents aging-associated cardiac dysfunction even when there is no difference in caloric consumption between TRF and ALF groups¹⁶. Second, while both TRF and caloric restriction are beneficial, they have unique and complementary benefits. Both TRF/TRE and caloric restriction consistently lead to weight loss in obesity⁴⁵, while TRF/TRE is beneficial for rhythmicity⁴⁶. Importantly, caloric restriction improves lifespan only if TRF occurs^47,48. The health benefits of TRF are present in multiple studies in both animal models and humans and demonstrate that TRF’s benefits are not limited to obesity prevention and weight loss, as aging and sleep dysfunction are critical risk factors for many metabolic disorders.

Together, these studies provide critical evidence for molecular mechanisms by which TRE could be beneficial. Specifically, TRF/TRE improve lipid and glucose metabolism, immune function, inflammation, insulin resistance, and modulate gut microbiome^{3,31,41–43,49–52}. New insights have also highlighted the importance of autophagy⁴⁶ and adipocyte thermogenesis⁵³ in animal models, providing new pathways to study in TRF/TRE. Additionally, transcriptomics comparing TRF to ALF have identified several pathways modified by TRF that could contribute to its beneficial effects, including clock genes, molecular chaperone TRiC/CTT complex, which is upregulated by TRF, and mitochondrial electron transport chain components, which are downregulated by TRF^3,31. Recent human studies have confirmed that TRE decreases genes involved mitochondrial regulation⁵⁴ and strengthens circadian clock gene rhythms⁵⁵ in subcutaneous adipose tissue. Additionally, transcriptomic analyses identified transcriptional regulation, small GTPase binding, and proteasome function as key pathways modulated by TRE^54,55. Thus, TRE has tremendous therapeutic potential and normalize the metabolic rhythms disrupted in metabolic disorders through many potential mechanisms, broadening its potential impact (Figure 1).

Figure 1.

Time-restricted feeding (TRF) to treat circadian dysfunction. A: Normally, people are active during the day, when there is light, and east most of their food, and less active during the night and eat little food. This leads to healthy rhythmic expression of clock genes and metabolic rhythms, and normal health. Inappropriate constant light-driven food-driven cues leads to circadian dysfunction, disrupted rhythms, and metabolic disorders like cardiovascular disease, accelerated aging, immune dysfunction, and obesity. TRF consists of fasting during the inactive period and feeding during the active period, in contrast to ad libitum feeding, where food is always available, and leads to improved circadian rhythms and improved outcomes associated with many metabolic disorders. B: TRF impacts several key protein and transcriptional pathways related to circadian and metabolic rhythms, which could underlie its beneficial effects.

Regulating Circadian Rhythms in Cardiometabolic Disorders With Time-restricted Feeding

Circadian rhythms misalignment, cardiovascular disease, and aging disorders

Key evidence in humans suggests that there may be a connection between circadian rhythm misalignment, cardiovascular disease, and aging. Circadian dysregulation likely contributes to diseases like obesity, type II diabetes, and sleep apnea⁵⁶. Disrupted circadian rhythms from shift work, sleep disorders, and genetic influences like clock gene polymorphisms increase risk for cardiometabolic diseases, potentially due to metabolic rhythm disruption⁵⁷. In particular, shift workers, like fire fighters, nurses, and other healthcare workers, and who account for more than 25% of the current workforce, have increased risk of obesity, type II diabetes, cardiovascular disease, metabolic syndrome, gastrointestinal disorders, Alzheimer’s disease, cognitive decline, and cancer^58–60. It is likely that circadian dysregulation contributes to the increase in risk factors for these metabolic disorders in shift workers^61–63.

Circadian misalignment also commonly occurs with aging, which contributes to many metabolic disorders. Some circadian rhythm dampening naturally occurs with aging, but modern lifestyle worsens this dampening²³. Aging leads to cardiac dysfunction and cardiovascular disease, and circadian misalignment aggravates these age-related cardiometabolic risks⁶⁴. Genetically modified mouse models have provided valuable insight into the relationship between circadian misalignment and cardiometabolic risks. For example, germline deletion of BMAL1 abolishes oscillation of both heart rate and blood pressure, leading to age-dependent cardiomyopathy^65,66. Similarly, cardiomyocyte-specific BMAL1 deletion in mice resulted in age-dependent dilated cardiomyopathy, diastolic dysfunction, proinflammatory gene expression and decreased life span⁶⁷. Thus, circadian disruption and aging can contribute to cardiac dysfunction, and specifically disrupting the clock in the heart is sufficient to cause cardiac dysfunction.

TRF/TRE suppress cardiometabolic risk

TRF and TRE can suppress cardiac dysfunction, likely by realigning circadian metabolic cues. Supporting this, high and frequent intake of energy-dense diet disrupts metabolic homeostasis and can increase cardiometabolic risk, alongside other genetic and environmental factors⁶⁸. TRF is beneficial for signatures of metabolic disorders like type II diabetes, high cholesterol, fatty liver, along with reducing cardiometabolic risks^3,69–71. Normally fed mice with constant access to food developed liver fibrosis with age, which is prevented by TRF. Even with a high-fat diet, TRF protects against obesity, hyperinsulinemia, hepatic steatosis, and inflammation^41,42. In Drosophila, which are a powerful genetic tool we and others use to study obesity and cardiovascular function, cardiac aging is significantly reduced by TRF. This holds true with a high fat diet, where flies on TRF still had better cardiac efficiency and decreased arrhythmia despite the increased metabolic stress due to higher caloric intake^3,31. In people with metabolic syndrome, 12 weeks of 10-hour TRE lowered blood pressure, LDL cholesterol, non-HDL cholesterol, and other markers of cardiometabolic health⁵¹. Another TRE study found that even just 4-weeks of TRE increased adiponectin and HDL cholesterol with reduced blood pressure⁷². In shift-worker firefighters at risk for cardiometabolic disease, 12 weeks of 10-hour TRE decreased VLDL particle size, hemoglobin A1C and blood pressure⁷³. Importantly, this study also found that TRE is feasible even for shift workers, which is promising for reducing the risk associated with shift work. Thus, TRF and TRE support circadian function, especially metabolic rhythms, which helps cardiovascular function and can control risk factors.

Circadian rhythms and the immune system

Chronic inflammation is a major pathophysiological factor in metabolic disorders and cardiovascular disease, and circadian rhythms are also closely linked with immune function. Recent findings point to Per2 as a key point of connection and while the precise mechanism of Per2 action is not known, it is required for rhythmicity of IFN-γ in spleen and serum, and in NK cell-mediated cytotoxicity⁷⁴. Per2 is also important for circadian-regulated changes in cytotoxic receptor expressions like Ly49C and Nkg2d in bone marrow cells⁷⁴. REV-ERBα also affects the production of inflammatory cytokines like IL-6 in response to endotoxin in rat and human macrophages⁷⁵. Additionally, the CLOCK:BMAL1 heterodimer controls expression of the PRR Toll-like receptor 9, which influences inflammation as well as innate and adaptive immunity^74,76. Other studies in Drosophila have reported that defense against bacterial infection was influenced by Timeless (Tim). In wild-type flies, resistance to S. pneumonia infection oscillates daily by upregulating phagocytosis at night, and Tim mutant flies were more prone to infection⁷⁷. In mammals, circulating hematopoietic cells, as well as hormones and cytokines in blood show circadian rhythm that oscillates according to rest-activity cycle of individual⁷⁸. For example, the level of hematopoietic stem and progenitor cells and most mature leukocytes peak during the resting phase whereas the acrophases of glucocorticoids, epinephrine, norepinephrine, and the pro-inflammatory cytokines TNF and IL-1β occur during the onset of the active phase. Even outside of animals, susceptibility to infection is circadian. In the plant Arabidopsis thaliana, resistance to bacterial pathogens has circadian regulation⁷⁹, and circadian clock-associated 1 (CCA1) influences the expression of R-gene-mediated resistance against downy mildew⁸⁰.

Many immune-related diseases’ symptoms show circadian characteristics. For example, rheumatoid arthritis symptoms are worse in the early morning and improve as the day progresses, which could be due to enhanced serum levels of TNF and interleukin-6 early in the day⁸¹. In both humans and mouse models, migration of lymphocytes in various parts of body also follow circadian rhythm⁸². For example, proliferation of lymphocytes in lymph nodes and spleen occurs during the rest phase, whereas in the thymus and spleen they are predominant during the active phase. Additionally, many circulating inflammatory markers have circadian rhythms and could contribute to circadian immune response³⁵. Shift work and circadian misalignment also increase systemic inflammation seen by the increase in circulating levels of IL-6 and hsCRP^62,83. Myeloid cell-specific deletion of Bmal1 provokes a proinflammatory response in mice, leads to a loss of oscillations of Ly6C^hi monocyte levels, and worsens chronic inflammation in diet-induced obesity⁸⁴. Additionally, overexpressing REV-ERBα or administration of a REV-ERBα/β agonist induces an anti-inflammatory response⁸⁵. Together, these results show that there are strong connections between circadian rhythms and immune function.

TRF/TRE boost immunity and insulin sensitivity

TRF can prevent or reverse dysfunction associated with inflammation in metabolic disorders. An eight week TRE study on resistance-trained males showed increase in adiponectin along with decrease in inflammation markers like TNF-α and IL-1β in the TRF group⁸⁶. Adiponectin is secreted by adipose tissues and has strong anti-inflammatory effects and improves insulin resistance⁸⁷. Insulin resistance and levels of cytokines like TNF-α, IL-6 can affect each other bidirectionally⁸⁸. Additionally, a 4-week study on elite endurance athletes reported similar modulation of some inflammatory markers like IL-6 and IL-1β and TNF-α by TRE⁸⁹. Finally, mice given a high fat diet showed dampened diurnal rhythms in food intake and body respiratory exchange ratio, while TRF improved their rhythms and respiratory exchange ratio⁴¹.

Beyond its clear role in metabolism, TRF also has positive effects in immune function in the context of aging. TRF increases adiponectin, and prevents insulin resistance and systemic inflammation⁸⁶. A 12-week study on young and old men showed decrease in hematocrit, total white blood cells, lymphocytes, and neutrophils along with reduction in natural killer cells after TRE, compared to pre-TRE values. Importantly, there was no negative consequence on muscle power output in both groups. This demonstrates that TRE can lessen systemic low-grade inflammation and age-related chronic ailments linked to immune dysfunction, without limiting physical endurance⁹⁰. Together, these results highlight the key role that timing of eating has in immune function, and the clear benefits that it can have in humans.

TRF/TRE in the management of obesity

Circadian rhythm disruption, metabolic dysfunction, cardiac disease, and inflammation are all significantly associated with obesity, which has a massive impact on health worldwide, even being compared to a pandemic⁹¹. Circadian rhythm dysfunction occurs in obesity and obesity throughout life is a major risk factor for cardiometabolic disorders with aging⁹². Additionally, inflammation is a critical and common component in obesity and may be the mechanism by which obesity increases risk for other diseases⁹³. In this review, we have described how metabolic and immunological parameters are improved by promoting the alignment of circadian rhythms with TRF, suggesting that it is likely to be beneficial for the treatment and prevention of obesity, which has been a major focus of the TRF/TRE fields.

In mice, TRF mitigates weight gain resulting from a high-fat diet and facilitates robust oscillation of genes involved in circadian rhythm⁹⁴. It improves insulin sensitivity and prevents many metabolic dysfunctions in obesity⁹⁴. These results are replicated in Drosophila, where TRF is beneficial in models of both diet-induced and genetic-induced obesity¹⁶. Furthermore, even in high-fat diet, TRF decreases the gene expression of inflammatory cytokines and the number of macrophages in adipose tissue, preventing an increase in the CD8+/CD4+ ratio in models of obesity⁹⁵.

While TRF has promising results in animal models, TRE is still in the beginning stages of testing in human studies of obesity. Recent studies have demonstrated some potential of TRE in the management of obesity and metabolic syndrome, though conflicting reports demonstrate the need to optimize TRE protocols to specific populations and desired outcomes. An observational study reported an association with eating in an 8- to 10-hour time window with a lower risk of weight gain and obesity, as well as hypertension and dyslipidemia⁹⁶. Similarly, 12 weeks of 10-hour TRE in patients with metabolic syndrome resulted in weight loss and fat loss, especially abdominal fat that is associated with increased cardiovascular risk⁵¹. In contrast, Lowe, et al. found that 12 weeks of 8-hour TRE in a heterogeneous sample of men and women resulted in slight but nonsignificant weight loss with no changes in estimated energy intake⁹⁷. In addition, there were few differences between the TRE and the control group, with no significant differences in fat mass, fasting insulin, glucose, hemoglobin A1C, or blood lipids. In a specific population of women with obesity, three-months of 8-hour TRE reduced weight, BMI, body fat and waist circumference compared with baseline, but reflected no changes in blood biomarkers associated with metabolic syndrome⁹⁸. In contrast, 12 month 12-hour TRE in low-income women with obesity associated with a hypoenergetic diet, there were no significant differences in weight loss between the two groups⁹⁹, which is consistent with the report by Liu, et al. that caloric restriction was similar to TRE⁴⁴. However, women who underwent TRE did have reduced waist circumference and body fat, compared to those who only had a low-calorie diet, indicating that long-term TRE may be beneficial, especially for low-income populations with obesity where it can be affordably adopted⁹⁹.

The clinical trials reported so far use different TRE interventions with different study times, with conflicting outcomes, making difficult to directly compare their results and make robust conclusions about the effects of TRE for obesity. Also, many of these studies have been for just 3 months, and it is likely that long-term intervention will result in larger results on weight loss and metabolism. However, it is consistently found that TRE is at least moderately beneficial for weight loss and metabolic parameters with no negative outcomes reported so far. Thus, TRE is promising for treating obesity in humans and further clinical studies are needed to optimize TRE protocols and identify the strongest effects of TRE on obesity in humans.

Concluding remarks

Metabolic disorders like obesity are incredibly common and treatments to prevent them are desperately needed as they are the leading cause of death worldwide. Here, we review diverse evidence that time-restricted feeding/eating could be beneficial in metabolic disorders. TRF plays an important role promoting circadian rhythms, cardiovascular function, metabolism, and immunity. All of these have important circadian and metabolic contribution, and TRF supports these key biological functions (Figure 2). Even beyond the important therapeutic implications, the studies described here demonstrate the critical roles that circadian rhythms play in health and disease and point to the importance of studying the biology underlying circadian rhythms.

Figure 2.

Circadian rhythms are critical for normal function and are disrupted in many metabolic disorders, including obesity, cardiovascular disease, aging, and immune dysfunction. TRF is beneficial in these disorders through several potential mechanisms. Images created in Biorender.

Going forward, it will be important to continue studying how circadian rhythms contribute to health and how misalignment between them contributes to diseases, especially obesity. The master clock in the central nervous system and clocks in the periphery likely interact in a bidirectional manner, so determining the best way to regulate their signaling is important. Additionally, it will be critical to study the interactions between metabolic disorders that are associated with circadian disruption. For example, obesity is not only associated with disorders with classic metabolic connections like cardiovascular disease and hypertension, but also with metabolic disorders like Alzheimer’s disease that are not typically primarily associated with metabolic dysfunction. Thus, it is critical to understand how different organs interact in metabolic disorders, how circadian misalignment between organs could contribute to altered metabolism and associated dysfunction, and how different metabolic disorders interact with each other. If promoting circadian rhythms and metabolism prevents or reverses disease course, it will be critical to determine the best way to do so. TRE is of particular interest, as it is a lifestyle intervention that would be much cheaper than many drug-based approaches, which removes that barrier of cost for persons from disadvantaged background or from low-income countries and can be easily adopted in the clinic. It will be important to optimize TRE protocols in humans to find the feeding-fasting pattern that has the most health benefits and promotes the important social benefit of eating together. In addition to how long to conduct TRE, it will be critical to identify the proper eating window length and timing. A small study recently started answering this question, comparing early TRE (‘eTRF’, eating from 06:00–15:00) and mid-day TRE (‘mTRF’, 11:00–20:00) for five weeks in healthy adults¹⁰⁰. Both TRF paradigms had similar reduced energy intake and body fat loss, though eTRF was more effective than mTRF to improve metabolic parameters, inflammation, and gut microbial diversity. Overall, TRE seems to be beneficial in circadian rhythm dysfunction, cardiometabolic disorders, aging, and obesity. Regulating circadian rhythms and metabolic rhythms with TRE is a promising approach that could have tremendous therapeutic impact, so determining if and how it prevents human disease is critical for improving human health.

Study Importance Questions.

• What is already known?

  • Circadian rhythm disruption is associated with cardiometabolic disorders and aging.
  • Time-restricted feeding and eating can help promote metabolic health and align circadian rhythms.
• What does this review add?

  • Connecting nutrition, circadian biology, and aging in cardiometabolic disorders, the leading cause of death in the U.S.
  • Showing that time-restricted feeding could be beneficial in metabolic disorders like cardiovascular and cardiometabolic dysfunction, aging, immune dysfunction, and obesity.
• How might this change direction or focus of clinical practice?

  • Shifts the paradigm away from work centered solely on diet composition and towards the importance of diet timing in cardiometabolic disorders and aging.
  • Shows that time-restricted feeding/eating could address the pressing need to investigate new approaches that can reduce mortality due to cardiometabolic disorders in humans.