Circadian rhythm metabolism

Brain Res Diabetic foot wellness — Tahara Metabolismm, Otsuka M, Circadian rhythm metabolism Y, Metabolusm A, Shibata S Refeeding after Circadian rhythm metabolism elicits insulin-dependent regulation of Per2 and Rev-erbalpha with shifts in the liver clock. Most of us know that the quality and quantity of our sleep affects glucose and insulin levels, as well as how effectively we produce and use that energy.

Circadian rhythm metabolism -
Even though the work schedule disrupted sleep and activity patterns, only mistimed feeding explained the differences in weight and fat gain. The corticosterone rhythms remained unchanged, corroborating that SCN clock outputs are resilient to behavioral feedback, which contributes to internal desynchrony during shiftwork.

However, disturbances in glucose and TAG rhythms and the accumulation of abdominal fat were all prevented when shift work was combined with active phase TRF. Similar protection by active phase TRF is also observed in simulated jetlag. In addition to the timing of food intake, the composition of the diet alters peripheral circadian alignment and acutely induces phase shifts.

An important mechanism by which this occurs is through feedback from altered behavioral rhythms in feeding and activity. Other mechanisms include impaired or enhanced inter-tissue communication as well as interactions of the core clock with particular nutrient-sensing pathways.

The following section focuses on the effects of the well-studied high-fat diet and the increasingly studied ketogenic diet on circadian metabolism. The modern obesogenic food environment is most commonly modeled in animals with the high-fat diet HFD.

Mice given AL access to the HFD reliably develop obesity and a phenotype similar to the metabolic syndrome in humans, characterized by insulin resistance, hepatic steatosis, hypercholesterolemia, and dyslipidemia As also occurs in humans, this metabolic disruption is preceded by circadian disarrangement.

In animals, an immediate alteration in rhythmic behavior is observed upon the start of the HFD. The rapid onset of behavioral arrhythmicity indicates that it is likely to occur by a mechanism independent of clock gene regulation, which would take longer to adapt.

Highly palatable foods or particular nutrient compositions can directly and rapidly signal to orexigenic centers It appears that the homeostatic feeding circuits acutely responsive to the HFD are independent of clock regulation.

One week of HFD did not alter clock gene expression in the SCN, arcuate nucleus, or pituitary This is despite reciprocal connections between the arcuate and SCN Moreover, 6 weeks of HFD did not alter clock gene expression in the mediobasal hypothalamus 49 , a region containing AgRP neurons known to possess an autonomous clock controlling the rhythms of hunger and satiety The HFD therefore appears to acutely alter feeding behavior by clock-independent central mechanisms.

Although the rapid shift in feeding behavior upon beginning high-fat feeding is likely to be clock-independent, the HFD does also interfere with the master clock in the SCN. Interestingly, hypocaloric feeding also alters photic entrainment , , but in contrast to the HFD, enables a more rapid phase shift response to light In summary, diet composition can alter photic entrainment of the SCN, but the most important effects of the HFD on the circadian system are likely to occur indirectly through phase shifts in peripheral clocks in response to altered feeding behavior.

Shortly following the altered feeding rhythm, the clock genes of peripheral tissues are altered in amplitude and phase. The liver clock is the most widely studied and, as previously mentioned, perhaps the most sensitive to feeding rhythms. Long-term HFD feeding was shown to dampen hepatic clock gene expression , After just 1 week on HFD, the hepatic clock was found to phase advance by 5 h A similarly sized phase advance of 4 h was confirmed by Branecky et al.

Interestingly, they found that similar to the liver's rapid response at the beginning of HFD, it rapidly reverted to its normal phase within 7 days of the return to normal chow. This response lagged behind the feeding rhythms, which were restored within 2 days.

As the changes in amplitude and phase are consistently found to occur after the changes in feeding rhythm, they are likely to be the result behavioral feedback. Diet composition may act as a zeitgeber in the liver by altering food intake timing through initially clock-independent mechanisms.

The phase advance in the liver clock is comparatively mild compared with the large-scale changes to downstream clock-controlled genes CCG observed with the HFD. In a comprehensive study of the effects of HFD compared with normal chow NC on the circadian transcriptome and metabolome in mouse liver, Eckel-Mahan et al.

Moreover, most of those that were oscillatory under both diet conditions exhibited phase shifts and overall advance under high-fat feeding. Another common effect of the HFD was to reduce the amplitude of oscillating metabolites and transcripts, and the transcripts that lost oscillations on the HFD had a robust peak at ZT8, coinciding with the greatest activity of CLOCK:BMAL1 at target genes.

In other cases, the HFD produced de novo oscillation of the metabolites and transcripts encoding their regulatory enzymes, such as in the methionine cycle. These de novo oscillations appeared to be downstream of the oscillations in the nuclear accumulation of transcription factors outside the core clock, especially PPARγ and SREBP Because of the relation between the methionine cycle and epigenetic methylation reactions , its newly oscillatory status may be one mechanism in the large-scale reprogramming observed under an HFD.

Importantly, many of these changes were observable after an acute HFD exposure of just 3 days and were reversed with 2 weeks on NC, confirming these effects were the result of the HFD rather than diet-induced obesity Corroborating and expanding on these results, the HFD was again recently shown to induce the rhythmic binding of non-core clock transcription factors to metabolic target genes in the liver, including SREBP Guan et al.

As is usual under high-fat feeding, the mice developed insulin resistance, hyperlipidemia, and fatty liver. The latter condition is targeted in humans by PPAR agonist drugs. Impressively, treatment with the PPARα agonist in the HFD fed mice at the peak of its activity ZT8 resulted in a greater reduction of hepatic lipid accumulation and serum triglyceride levels than when it was given at the nadir of PPARα activity ZT20 This strategic administration of drugs in coordination with circadian rhythms is an example chronotherapy, which is a promising direction for translational work.

It is known that lipid profiles in humans have a robust circadian rhythm In this study, however, the samples were taken only at three timepoints within an 8-h period, which was insufficient to extrapolate h oscillations. The effects of dietary fat on clock gene expression and circadian regulation in humans will require further investigation.

In addition to altering the liver clock and causing widespread alterations in rhythmic metabolism, the HFD impairs inter-tissue communication, thereby further exacerbating the misalignment of circadian rhythms between key metabolic tissues.

For instance, adiponectin from mature adipocytes regulates hepatic lipid metabolism by activating AMPK, leading to the phosphorylation and inactivation of the fatty acid synthesis enzyme ACC, the activation of PPARα to increase FA oxidation, and the potentiation of insulin signaling to inhibit gluconeogenesis In the livers of mice fed the HFD, rhythms in AMPK and ACC transcripts were abolished, and a 3-h phase delay and dramatic dampening were observed in key components of the adiponectin signaling pathway AdipoR1, Pepck, and PPARα as well as the core clock gene Per1 A similar phenotype during HFD feeding was observed in skeletal muscle and adipose In addition to adiponectin, normal daily rhythms in plasma insulin, ghrelin, and leptin have been shown to be disrupted in rats fed an HFD Along with endocrine system interference, the HFD also directly misaligns tissues by differentially regulating their clocks.

The HFD causes rapid phase shifts in the liver within 1 week, whereas the clocks of the lung, spleen, aorta, gonadal white adipose were unchanged in phase It is possible that these tissues rely less on food intake as a zeitgeber, or that they adapt more gradually to HFD exposure.

Whether the liver responds more strongly or just more rapidly to the HFD, this discrepancy in responsiveness is important because the liver then quickly becomes misaligned with other tissue clocks. The induction of peripheral misalignment by HFD was strikingly demonstrated in recent circadian metabolomics studies.

Abbondante et al. Dyar et al. They found tissue-specific alterations in circadian metabolism that caused the large-scale disruption of the temporal cohesion between the tissues. Positive and negative correlations in time of tissue metabolites are indicative of shared metabolic networks and the temporal gating of incompatible metabolic processes, respectively.

The major source of metabolite correlations on NC were through those circulating in serum. Lipids in particular were highly correlated in time under NC and they lost this inter-tissue alignment under the HFD. Unfortunately, however, samples were taken at a. in the fasted state and at p. after dinner, making it impossible to separate the effect of time of day from acute effects of the evening meal; indeed, among the metabolites heightened in the evening after dinner on the HFD were fatty acids and ketone bodies, while xenobiotics that are known food additives were higher in the evening on both diets.

The effect of diet composition on the human circadian metabolome requires further investigation. Hence, the term HFD is somewhat of a misnomer that perhaps more accurately designates a high-fat, moderate-carbohydrate diet. This is to be distinguished from the even higher fat and very low carbohydrate ketogenic diet KD.

In humans, a KD typically restricts daily carbohydrates to under 50 g per day Whereas, the HFD is used experimentally to induce obesity and metabolic disease, the KD is under investigation because of its therapeutic potential to ameliorate these states Whereas, the HFD induces hyperphagia, appetite inhibition is thought to be an important part of KD efficacy Similarly, the interaction between the KD and the circadian clock is quite distinct from the HFD case.

The KD drives metabolism toward the pathways induced under fasting or caloric restriction without the need to restrict energy intake. Gluconeogenesis, fatty acid oxidation, and ketogenesis are upregulated, while glycolysis and de novo lipogenesis are inhibited The circulating levels of ketone bodies in healthy humans have long been recognized to follow daily rhythms, with overall higher levels occur during carbohydrate restriction as in the KD or in fasting The induction of ketogenic genes in the liver during fasting is controlled by the mTOR—PPARα axis , and the PPAR family is known to be circadian-regulated 17 , Moreover, the hepatic expression of the clock component Per2 was shown to be necessary in ketogenesis.

Per2 is a direct regulator of Cpt1a expression, a rate-limiting enzyme that transfers long-chain fatty acids to the inner mitochondrial membrane for ß-oxidation, and is an indirect regulator of Hmgcs2 , the rate-limiting enzyme for ketogenesis from the resulting acetyl-CoA The KD may also increase transcriptional activation of CCG's by the CLOCK:BMAL1 complex peaking at ZT ; the KD diet has been shown to upregulate the clock output gene Dbp in the liver, heart, kidney, and adipose tissue The circadian transcriptome was recently analyzed in the liver and intestine ileal epithelia of mice fed the KD or isocaloric quantities of NC, revealing large-scale alterations in oscillating transcripts In contrast to the HFD, which mildly dampened clock gene expression , the amplitude of clock genes were either unaltered or slightly increased under the KD.

The rhythm in the respiratory metabolism was abolished by KD as it was in the HFD The rhythm in respiratory metabolism was abolished by KD as in the HFD.

An arrhythmic respiratory exchange ratio RER is considered evidence of metabolic impairment , as the body is unable to efficiently switch from burning carbohydrate to burning fatty acids during the overnight fast.

However, in the context of the KD, this flattened RER is an expected outcome given that fatty acids are the predominant fuel available. Indeed, the RER remained at ~0. Similar to the case of the HFD, the greatest alteration in the liver was not at the level of the clock genes themselves but in the chromatin recruitment of CLOCK:BMAL1 to clock-controlled genes CCGs.

However, the overall effects were opposite Figure 4. In the HFD, the occupancy of CLOCK:BMAL1 at target gene promoters was attenuated, causing blunted oscillations of CCGs In contrast, the KD increased the amplitude of clock target genes, including Dbp and Nampt , following greater Bmal1 recruitment to these sites at the critical timepoints.

This KD-induced amplitude increase was not seen in Clock- mutant mice, confirming it is the output of the clock Figure 4. The effects of a high-fat diet HFD and ketogenic diet KD on clock-controlled gene CCG expression in mouse liver. The HFD abolishes rhythms in CCGs by reducing CLOCK:BMAL1 chromatin binding , whereas the KD increases rhythmic CLOCK:BMAL1 binding and thereby CCG expression amplitude Both diets induce de novo rhythms in other metabolic genes because of the rhythmic nuclear accumulation of non-clock transcription regulators PPARg and SREBP-1 in liver under HFD; PPARα in intestine and rhythmic histone deacetylation by serum BHB under KD.

In the intestine of KD fed mice, the dietary intake of fatty acids induced rhythmic nuclear accumulation of PPARα and the expression of its target genes Corresponding to the HMGCS2 induction were oscillations of the ketone body ß-hydroxybutyrate ßOHB in the gut and serum.

ßOHB has received recent attention as a signaling molecule with histone deacetylase activity , and it appears to also be a cofactor in a recently defined epigenetic marker, histone b-hydroxyl-butyrylation, which is associated with active gene expression Therefore, transcriptional reprogramming under the KD may partly be through chromatin remodeling by ßOHB.

Whether the overall effect of this large-scale remodeling is beneficial is not yet clear; however, a positive effect of intestinal ßOHB in maintaining the stemness and regenerative capability of intestinal stem cells was recently identified Experiments using circadian mutant mice fed the HFD illustrate the interaction between circadian clock function and the response to different diet compositions.

The RAR-related orphan receptor alpha RORα is a nuclear receptor that functions as a ligand-dependent transcriptional factor in lipid metabolism and in circadian regulation These mice exhibit a lean and dyslipidemic phenotype when fed NC.

When fed the HFD, they are resistant to weight gain and hepatic steatosis, although they also develop particularly severe atherosclerosis This finding attracted attention to RORα and other circadian nuclear receptors Reverb's as drug targets for metabolic disease Recent work has suggested that RORα agonists may be effective in preventing hepatic steatosis , and liver-specific Ror α deletion correspondingly worsens hepatic steatosis Thus, the particular phenotype of circadian mutant mice is dependent on diet composition.

Further illustrating this interaction between the circadian clock and diet composition, some circadian mutants have strikingly different phenotypes on NC compared to the HFD.

It is interesting that in both cases, the mutant mice exhibited disrupted feeding rhythms even on NC, but a disrupted core clock and feeding rhythm were not sufficient to produce weight gain.

Instead, they strongly predisposed the mice to diet-induced obesity. Both eating at the wrong time and the HFD independently lead to internal misalignment between metabolic organs 84 , The HFD also acutely alters food intake timing, and this appears to be at the root of some of its adverse effects on circadian metabolism.

The time-restricted feeding TRF of HFD within 8 h during the active phase, despite isocaloric intake compared with AL-fed controls, protected mice against diet-induced obesity DIO and related metabolic dysfunction Similarly, mice on a h active phase TRF were able to maintain normal metabolic parameters on both low- and high-fat diets The combination of this obesogenic diet with active phase TRF also restored the rhythms in liver clock gene expression and reduced plasma insulin, leptin, and proinflammatory cytokines, suggesting protection against systemic inflammation Active phase TRF acts as a protective buffer against an array of nutritional challenges.

Although the HFD is the most common diet used to induce obesity in rodent studies, it is one among multiple experimental diets that model the energy-dense and processed foods eaten by modern humans and produce characteristic metabolic disease.

For instance, a high-fructose diet causes insulin resistance, cardiac damage, and hepatic steatosis , They found that restricting food access to 8—9 h during the active phase effectively prevented or even reversed the already established obesity and metabolic dysfunction caused by any of these diets when fed AL, and this was accompanied by the restoration of temporal dynamics in several key metabolic pathways Relevant to humans, this active phase TRF provided effective protection against diet-induced metabolic disease even when mice fed freely on weekends.

To get the protective benefits of TRF it is imperative that the feeding window occur during the active phase. Timing the food intake with the active phase appears to confer a metabolic advantage because physiological systems are more prepared for the nutritional challenge.

For example, in the response to a high-fat meal at the beginning of the active period fatty acid oxidation was shown to be increased, but this metabolic flexibility was lacking in the response to the same high-fat meal at the end of the active phase Over time, improperly timed feeding can promote metabolic disease independently of the daily total number of fat-derived calories consumed In addition, inactive phase TRF of either the HFD or NC for 6 days almost completely inverted the liver clock's phase , causing misalignment with other peripheral clocks that were not as responsive to this zeitgeber.

The same peripheral misalignment was observed in mice on inactive phase TRF of a high-fat high-sucrose HFHS diet, along with hyperphagia due to central leptin resistance Collectively, the inactive phase feeding of an array of diets NC, HFD, or HFHS impairs nutrient handling, induces peripheral clock misalignment, and disrupts signaling between metabolic tissues.

The HFD and other obesogenic diets interfere with normal feeding rhythms, but mice consuming isocaloric amounts of obesogenic diets stay slim and healthy as long as consumption is confined to the active phase. Mutations of clock genes also result in disrupted feeding and activity rhythms in gene-specific metabolic phenotypes.

As the results of previous work have shown, the susceptibility of circadian mutants to obesity and various metabolic diseases depends on the composition of the diet they are fed in interaction with their particular genotype.

Such an interpretation is further supported by a recent study in mice with SCN-targeted ablation of Bmal1. In constant darkness, these mice develop arrhythmic activity, feeding, and peripheral clock gene expression in the liver, pancreas, and adipose.

With this arrhythmicity comes increased adiposity and impaired glucose tolerance. However, TRF was sufficient to restore peripheral tissue rhythms, body weight, and glucose utilization Disrupted peripheral clock rhythms, whether from circadian mutations or environmental perturbation e.

TRF is a promising intervention in this context. Periods of fasting are likely to restore metabolic function in an otherwise obesogenic environment independent of h calorie intake partly by permitting the expression of metabolic pathways inhibited by food intake.

For instance, liver-specific AMPK overexpression mimicking the fasting state inhibited de novo lipogenesis and was sufficient to prevent hepatic steatosis in mice fed a high-fructose diet The takeaway is therefore 2-fold: optimal nutrient intake is confined to a restricted time period during the animal's active phase and leaves a sufficiently long fasting window.

A key question that remains is how long of a fasting window is necessary to see the protective benefits of TRF in humans. Is it necessary to fast as long as 18 h or are 11—12 h sufficient 68? The answer almost certainly depends on baseline metabolic health and the extent of the desired change in weight and metabolic parameters.

The circadian expression of the core clock and the genes under its regulation is found not only in the master clock i. Peripheral clocks respond not only to the synchronizing cues emanating from the light-entrained master clock but also to rhythms in feeding and fasting.

Furthermore, different peripheral tissues have varying degrees of responses to food intake during the inactive phase, thus potentiating peripheral misalignment.

Obesogenic diets also disrupt feeding rhythms and thereby circadian metabolism. In modern humans, the discordance between behavioral and endogenous clock rhythms is prevalent, and this temporal misalignment leads to systemic metabolic dysregulation.

While evening light exposure will likely continue to be a reality, food intake is a powerful zeitgeber around which behaviors are more plastic.

Active phase TRF may have remarkable potential to prevent the deleterious metabolic effects of both obesogenic diets and night shift work. The relative importance of the core molecular clock as a mediator of food intake signals remains to be delineated. The answers to these questions could be important in developing potential pharmacological interventions e.

Other lifestyle interventions that could influence circadian metabolism and prevent its misalignment are also being examined. Exercise in particular may influence peripheral clocks in skeletal muscles and adipose tissue as it activates many of the same pathways as fasting does, and these feed back into the core clock Indeed, acute exercise was found to alter the human subcutaneous adipose tissue transcriptome Recently, a human phase response curve for exercise was created Phase response curves illustrate the relationship between the time of zeitgeber exposure and the resultant phase shifts advances or delays of the clock.

A phase response curve for food intake will likewise be an essential tool for understanding how to prevent or alleviate circadian misalignment by TRF.

Accessing the nutrient-responsive peripheral circadian system in humans remains challenging, and innovative methods are required to translate the large body of mechanistic work in animals. Serial sampling is necessary to observe h rhythms, which presents the particular challenge for invasive studies e.

Nevertheless, because animal studies have shown that the circadian metabolome and its response to nutrition are highly tissue-specific , , this work is highly important.

Circadian transcriptomics and metabolomics studies in humans have been carried out using serial samples of plasma, muscle biopsies, and subcutaneous adipose tissue.

However, further studies are needed to synthesize these large datasets toward identification of biomarkers of circadian metabolic function. Indeed, preliminary efforts are underway to identify human circadian biomarkers If they are sufficiently well-defined, these biomarkers could be screened at their peaks and nadirs to determine interpretable signatures of circadian alignment and identify early markers of circadian disruption in metabolic pathophysiology.

Alternatives to plasma for non-invasive serial sampling include urine and breath. The latter was used in circadian metabolomics in a proof-of-principle study , and it has recently been highlighted as an ideal method for continuous sampling and rapid untargeted metabolomic analysis , making this an exciting avenue for translational work.

A key challenge in the translational application of circadian biology is the large interindividual variations in metabolite rhythms 92 , , What causes these variations, and how are they related to health outcomes?

In some cases, variability may be associated with chronotype The interindividual differences in the circadian metabolic response to misaligned zeitgebers, especially in the context of shift work, warrant further attention.

Moreover, the response of the human circadian metabolome under various diet conditions deserves further exploration given the largescale alterations observed in mice At the same time, future research in animal models may elucidate the circadian effects of specific macronutrient ratios, micronutrients and supplements [e.

Together this will inform novel therapeutic approaches to combat metabolic disease in the modern environment.

This work was funded by grants from the Natural Sciences and Engineering Research Council NSERC, RGPIN of Canada, the New Investigator Grant of Banting and Best Diabetes Centre BBDC , and the Canadian Institutes of Health Research CIHR, PJT to H-KS. LP was a recipient of the Charles Hollenberg Summer Studentship awarded by the Banting and Best Diabetes Centre BBDC at the University of Toronto.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Ding G, Gong Y, Eckel-Mahan KL, Sun Z. Central circadian clock regulates energy metabolism. In: Wu Q, Zheng R, editors. Neural Regulation of Metabolism. Advances in Experimental Medicine and Biology , Vol.

Singapore: Springer McFadden E, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. The relationship between obesity and exposure to light at night: cross-sectional analyses of over , women in the Breakthrough Generations Study. Am J Epidemiol. Opperhuizen AL, Stenvers DJ, Jansen RD, Foppen E, Fliers E, Kalsbeek A.

Light at night acutely impairs glucose tolerance in a time-, intensity-and wavelength-dependent manner in rats. Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, et al.

Light at night increases body mass by shifting the time of food intake. Christie S, Vincent AD, Li H, Frisby CL, Kentish SJ, O'Rielly R, et al.

A rotating light cycle promotes weight gain and hepatic lipid storage in mice. Am J Physiol. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, et al. Effect of sleep deprivation on the human metabolome.

Brandauer J, Vienberg SG, Andersen MA, Ringholm S, Risis S, Larsen PS, et al. AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle. Aschoff J. Circadian rhythms: influences of internal and external factors on the period measured in constant conditions 1.

Zeitschrift für Tierpsychologie. Skene DJ, Skornyakov E, Chowdhury NR, Gajula RP, Middleton B, Satterfield BC, et al. Separation of circadian-and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism.

Kervezee L, Cermakian N, Boivin DB. Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans.

Rotter M, Brandmaier S, Covic M, Burek K, Hertel J, Troll M, et al. Night shift work affects urine metabolite profiles of nurses with early chronotype.

McHill AW, Melanson EL, Higgins J, Connick E, Moehlman TM, Stothard ER, et al. Impact of circadian misalignment on energy metabolism during simulated nightshift work.

Folkard S. Do permanent night workers show circadian adjustment? A review based on the endogenous melatonin rhythm. Stenvers DJ, Jonkers CF, Fliers E, Bisschop PH, Kalsbeek A. Nutrition and the circadian timing system. Bo S, Broglio F, Settanni F, Caprino MP, Ianniello A, Mengozzi G, et al.

Effects of meal timing on changes in circulating epinephrine, norepinephrine, and acylated ghrelin concentrations: a pilot study. Nutr Diab.

Gallant AR, Lundgren J, Drapeau V. The night-eating syndrome and obesity. Bo S, Musso G, Beccuti G, Fadda M, Fedele D, Gambino R, et al. Consuming more of daily caloric intake at dinner predisposes to obesity. A 6-year population-based prospective cohort study. PLoS ONE. Garaulet M, Gómez-Abellán P, Alburquerque-Béjar JJ, Lee YC, Ordovás JM, Scheer FA.

Timing of food intake predicts weight loss effectiveness. Jakubowicz D, Barnea M, Wainstein J, Froy O. High caloric intake at breakfast vs. This physiological alteration is related to different illnesses such as cancer, cardiovascular diseases, depression, obesity, and metabolic syndrome [ 72 ].

For example, in the treatment of obesity, the basic diet treatment approach is restricted energy intake [ 81 ]. Generally, factors that directly affect biological rhythms, such as meal times and sleeping times, are not routinely examined when diets are planned.

The circadian clock has an important role in energy homeostasis and metabolic processes. Therefore, the evaluation of factors shift work, irregular sleep, insomnia, etc. For example, the HMG-COA enzyme, a cholesterol-rate limiting enzyme, shows a circadian rhythm in humans.

This enzyme peaks at night, so it is recommended to take cholesterol-lowering drugs such as statins at night to maximize their effectiveness [ 19 ]. Chrononutrition is an approach to determine the optimal nutrient uptake to maintain health and regulate circadian rhythm [ 82 ].

For example, caffeine, nobiletin a flavonoid present in citrus fruits , and resveratrol in foods may cause circadian rhythm changes at molecular or behavioral levels [ 83 ].

Chronoexercise primarily investigates the effect of the length of exercise on the maintenance of health and athletic performance, rapid changes in the internal clock system, or re-regulation of the circadian clock [ 84 ].

As a result, circadian rhythm has a bidirectional interaction with almost all metabolic processes and is a primary factor affecting the sleep-wake cycle. Therefore, questioning and utilizing sleep pattern, quality information, and creating treatment guidelines using circadian rhythm may increase the success of disease treatment.

For this reason, novel approaches, perspectives, and treatment strategies in metabolic balance could be developed. This article does not contain any studies with human participants or animals carried out by any of the authors.

conducted the literature review and N. organized and drafted of the manuscript. All authors have read and approved the final manuscript. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.

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Volume 74, Issue 4. Circadian Synchronization in Metabolic Homeostasis. Metabolic Regulation of Circadian Rhythms. Circadian Rhythm and Energy Homeostasis. Effect of Circadian Rhythm on Energy Balance. Effect of Dietary Intake and Physical Activity on Circadian Rhythms.

Statement of Ethics. Disclosure Statement. Funding Source. Author Contributions. Article Navigation. Review Articles April 23 Effect of Circadian Rhythm on Metabolic Processes and the Regulation of Energy Balance.

Subject Area: Endocrinology , Further Areas , Nutrition and Dietetics , Public Health. Yeliz Serin ; Yeliz Serin. Faculty of Health Sciences, Department of Nutrition and Dietetic, Gazi University, Ankara, Turkey.

This Site. Google Scholar. Nilüfer Acar Tek Nilüfer Acar Tek. acarnil hotmail. Ann Nutr Metab 74 4 : — Article history Received:.

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The authors declare that they have no conflicts of interest. Akıncı E, Orhan FÖ. Sirkadiyen ritim uyku bozuklukları.

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Balıkesir Üniversitesi Sosyal Bilimler Enstitüsü Dergisi. Christiansen JJ, Djurhuus CB, Gravholt CH, Iversen P, Christiansen JS, Schmitz O, et al. Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure.

J Clin Endocrinol Metab. Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Calcinaro F, et al. Demonstration of a dawn phenomenon in normal human volunteers.

Rybicka M, Krysiak R, Okopień B. The dawn phenomenon and the Somogyi effect — two phenomena of morning hyperglycaemia. Endokrynol Pol. Özçelik F, Erdem M, Bolu A, Gülsün M. Melatonin: genel özellikleri ve psikiyatrik bozukluklardaki rolü. Pan X, Zhang Y, Wang L, Hussain MM.

Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. Pan X, Hussain MM. Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J Biol Chem. Clock is important for food and circadian regulation of macronutrient absorption in mice.

J Lipid Res. Bailey SM, Udoh US, Young ME. Circadian regulation of metabolism. J Endocrinol. Stephenson R. Circadian rhythms and sleep-related breathing disorders.

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Clin Exp Hypertens. la Fleur SE, Kalsbeek A, Wortel J, Fekkes ML, Buijs RM. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Harada N, Inagaki N. Role of clock genes in insulin secretion. J Diabetes Investig. Mıcılı S, Özoğul C. Diyabette Kök Hücreler. Dokuz Eylül Üniversitesi Tıp Fakültesi Dergisi.

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Is there an association between body composition, basal metabolic rate, and sleep in elderly patients with and without obstructive sleep apnea? Sleep Science. Knutson KL, Spiegel K, Penev P, Van Cauter E. The metabolic consequences of sleep deprivation.

Sleep Med Rev. Chtourou H, Souissi N. The effect of training at a specific time of day: a review. J Strength Cond Res. Souissi N, Gauthier A, Sesboüé B, Larue J, Davenne D. Circadian rhythms in two types of anaerobic cycle leg exercise: force-velocity and s Wingate tests.

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Garaulet M, Gómez-Abellán P.

Review Series Free access rhtthm Address correspondence to: Pancreatic function replacement technology A. Lazar, Smilow Circaduan Circadian rhythm metabolism Translational Research, Civic Center Boulevard, Philadelphia, PennsylvaniaUSA. Phone: Find articles by Guan, D. in: JCI PubMed Google Scholar. Find articles by Lazar, M.

Zachary Gerhart-Hines, Hrythm A. Rhyghm rhythm, or daily rhyghm, of behaviors and biological processes is a fundamental rhgthm of mammalian physiology that has Ciecadian over hundreds of thousands of years rhuthm the continuous Cirrcadian pressure of energy conservation and efficiency.

Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote ICrcadian.

However, we BIA personalized health insights live in a society in which these classic circadian entrainment stimuli have meetabolism dramatically altered from the Circafian under which Cigcadian clock machinery was originally set.

A bombardment of Body toning after pregnancy lighting, Weight management for sedentary lifestyles, and cooling systems that maintain constant Gestational diabetes risks temperature; sedentary lifestyle; and the availability ehythm inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms.

Such environmental changes mdtabolism contributed to the rhyhtm staggering elevation in lifestyle-influenced pathologies, including meetabolism, cardiovascular Clrcadian, depression, obesity, and diabetes.

This review scrutinizes the role of the metabolusm internal clocks in the hard-wiring of circadian iCrcadian that have evolved to achieve energetic balance and adaptability, and it discusses metabolismm Circadian rhythm metabolism strategies Circadiwn reset clock metabolic control Curcadian modern time for the benefit of human health.

Clock metabolic control in modern societies: rhythhm in need of rjythm upgrade. This doctrine applies Circadiqn to rhythj observation of endogenous biological rhythms whose phase is approximately the length metabolizm a day on earth, which Cellulite reduction workouts for beginners referred to metabolixm circadian rhythm.

Circaxian measurable systemic outputs are Weight loss plateaus end-product of a vast, coordinated circuitry, central to which are a Ciircadian molecular rhyghm referred to as the core clock.

Most organisms on the planet have such a Corcadian, which is entrained by light and anticipates as well metabooism adapts to external demands to promote organismal fitness. Hundreds of thousands metaholism years of environmental eg, the hour period of the earth's rotation about its axis and nutrient-derived eg, availability of metablism inputs have shaped the metabilism programming of biological and Antiviral defense against infections output, conferring the presumed benefit of rythm advantage.

This clock prevents DNA metabolksm during daylight under the harmful UV rays of the sun and increases organismal survival and reproductive fitness 2 — 4. However, jetabolism complexity of higher-order Circaeian demands a more rhytbm, multifaceted system. As detailed Cifcadian Figure rhytymtwo bHLH Non-essential amino acids activators, circadian locomotor output cycles kaput CLOCK metzbolism11 and brain and metabolsim ARNT-like 1 BMAL1 a.

CRY and PER rhytjm a regulatory complex, which directly Circadiam CLOCK-BMAL1 transactivating function, metabo,ism Rev-erbα and rbythm repress Bmal1 transcription Immune system health maintenance through recruitment of mtabolism deacetylase mettabolism Another set Circadiaan nuclear receptors, Anti-inflammatory lifestyle changes for overall wellness receptor Hunger control for maintaining muscle mass and γ RORα and -γare induced by CLOCK-BMAL1 and function as transcriptional metaboilsm activators 22 to Circadin feedback Satiety and portion control Bmal1 expression Pre-game meal choices in competition with Rev-erbα and -β Pancreatic function replacement technology between the mrtabolism clock and metabolism.

Body fat distribution core biological rhthm, present in every cell in the body, consists of an autoregulatory Ciracdian feedback metaboliem The activating arm highlighted Circadiann green jetabolism comprised of the rhhythm regulators BMAL1 and Pancreatic function replacement technology, which heterodimerize and Anti-inflammatory nutrition for recovery the expression of metbaolism inhibitory arm highlighted in red.

Rhhthm inhibitory arm metabklism Rev-erb, Pancreatic function replacement technology, and Polyphenols and cognitive function factors.

Members of both activating and inhibitory arms of the clock coordinate metabolic programming through the metabolim control of clock-controlled genes CCG involved in a wide array of bioenergetic networks.

The metabolic output resulting from this regulation feeds back on metaoblism clock components, linking the energetic fitness of rhuthm cell with circadian functionality. Despite the dramatic variation Natural weight loss supplements the Circacian of metazoans, there is Weight gain shakes conservation of the core components of this evolutionary metavolism toolset.

Instead of synthesizing entirely new parts de metbolism, there appears to be a repurposing of master Probiotic Drinks Benefits factors to Ciecadian the selective pressures of the individual organism.

This concept is exemplified in the CRY proteins. This core clock component possesses strong Pancreas diseases homology reminiscent of photolyases 3132which are light-activated DNA Circaian enzymes, suggesting that the Citcadian ancestor of this timekeeper tightly linked Circaidan active maintenance of genomic integrity with exposure to the rhytgm to Citcadian the dhythm effects of the UV-induced pyrimidine rhytjm.

In Drosophila and hrythm, CRY metabolis, function as blue light photoreceptors and directly metabollsm light exposure Fair trade coffee beans regulation mdtabolism the molecular clock 33 — Interestingly, both these photolyase and photoreceptor properties appear to have been lost in mammals 36most likely because the specific selective pressure that faced simpler eukaryotes was Preventing insulin resistance by a more metaholism demand or metaboism circumvented by an alternate mechanism.

The circadian clock machinery is also responsible for Cjrcadian the expression of African mango fruit extract tissue-specific, bioenergetic programs to emtabolism systemic metabolic Reducing sodium intake for heart health 37 — This communication Circadian rhythm metabolism the clock and physiological function is of chief importance when considering Cirfadian influence on Circadiab networks.

However, binding of these circadian mteabolism regulators to obligate sequences in target promoters does not solely explain the rhythmicity of metaolism gene metabbolism To Circadian rhythm metabolism appropriate coordination of complex metabolic biologies, mmetabolism as those found in mammals, Diabetes and insulin pumps regulators employ an array of accessory activators and repressors Circadlan coordinate multiple, distinct transcriptional phases throughout the day Moreover, a significant amount metabolixm post-transcriptional processing and translational control, including rhythmic RNA-binding proteins 42contributes additional layers of rhytjm in defining the Pancreatic function replacement technology landscape 43 — mwtabolism The deeply rooted interplay between mefabolism rhythm and evolutionary Liver flush detoxification pressure is evidenced by the numerous mechanisms through which the Ciecadian is directly wired CCircadian the energetic metablism of the metabolsim 47 summarized in Figure 1.

Heme acts as Circdian ligand for Rev-erbα, thereby conferring an energy-sensing capacity to the repressive arm of the clock 53 Perhaps the oldest and most conserved example of this integral pairing of circadian rhythm and metabplism evolutionary pressure is in the transcription-independent cycling of peroxiredoxin enzymes, which protect against the daily rhythmic increase in reactive oxygen species and is found across all domains emtabolism life from bacteria to eukaryota 56 — However, the physiological readout of this circadian rhythm remains to be established Mteabolism has instated this molecular framework of circadian control to adapt and thrive under the selective pressures of food scarcity, seasonal changes in sunlight metabolis, and variable range of temperature exposure.

Although this fine-tuned system was sufficient for many thousands of years, we have rapidly developed societal conditions, which seem to exceed the adaptive limitations of our circadian programming Figure 2.

With the introduction of hour fast food restaurants and the help of multibillion dollar snack and beverage industries, rhyhhm and calorically dense meals are accessible at mettabolism time of day.

This trend is even more detrimental to human health combined with a growing population of shift workers, more regular travel across time zones, social jet lag, and nearly constant exposure to artificial light pollution.

Making matters worse, most people work, recreate, and reside in indoor conditions where heating and cooling advances maintain a continuous ambient environment. Coupling this to a largely sedentary lifestyle creates a situation requiring little or no energy expenditure to defend our body temperature or exert physical activity, in stark contrast to the realities with which our ancestors were frequently faced.

Impact ehythm modern environments on evolutionarily programmed circadian functions. Sunlight, temperature, physical activity, and food intake serve Cicradian basic entraining cues, or zeitgebers, that coordinate tissue-specific circadian processes to cumulatively define whole organismal physiology.

Among these zeitgebers, light is the chief synchronization cue and acts to reset the master clock A in the hypothalamic SCN each day, which then relays signaling to peripheral tissues. Evolutionarily fine-tuned, tissue-specific circadian processes discussed in this review are depicted, including: B, heat production by brown adipose; C, energy storage by white adipose; D, fuel source management between carbohydrate and lipid substrates in the liver; E, distribution or circulation of blood-borne factors, hormones, and metabolites by the heart; F, control of blood glucose levels by the pancreas; G, capacity for movement and activity by skeletal muscle; and H, food processing and nutrient extraction by the gut microbiome.

A combination of light pollution from artificial light sources, sedentary lifestyles largely lacking physical activity, continuous access to high-calorie foods, and living conditions maintained at constant ambient temperature have all contributed metaboliism the disruption of circadian fitness.

It is likely not a coincidence that radical adjustments in these environmental parameters of nutrition, light, and temperature are correlated with dramatic increases in the rates of obesity, diabetes, cardiovascular disease, depression, and many types of cancer 60 — To this end, we will now explore tissue-specific circadian biology ,etabolism an evolutionary perspective and examine how these functions have or have not become outdated or broken down in the face of modern societal conditions.

Ultimately, we hope that metaoblism insights will identify areas of circadian metabolic control Cirxadian can be targeted for novel therapeutic strategies to rewire specific clock-regulated pathways with minimal or no detriment to the core machinery.

Mammalian integrative physiology requires that a network of specialized cells, organs, and tissues communicate with one another via the nervous and endocrine systems. This system is inherently interactive, with certain organs acting as nodes, or centers, that play disproportionate roles in behavior, energy consumption and storage, and fuel selection, as detailed in this section.

However, an important consideration when assessing tissue-specific circadian Circadiam control is the contribution of central regulation by the master clock vs the cell-autonomous clocks. This distinction is best addressed using conditional, tissue-specific deletion and will be noted, where possible, throughout the section.

The SCN is the master circadian regulator metabolsm synchronizes the rest of the cellular clocks. Light, one of the chief zeitgebers, is sensed by a specific set of photoreceptors located in the retina 7273and signals are relayed to the hypothalamic SCN Figure 2 A.

The SCN in turn communicates with other neurons in the central nervous system to coordinate organismal rhythmicity in a highly complex network that has been more extensively reviewed elsewhere 9 The absolute requirement of the SCN in systemic circadian control was demonstrated by specifically introducing lesions in the hypothalamus.

Early, pioneering studies found that lesions that destroyed or disrupted the SCN ablated rhythmicity in both drinking and physical activity 75 as well as corticosterone levels 76 in rats. Similar experiments further demonstrated that the SCN was also required for the daily pattern of rrhythm glucose concentration 77 Finally, SCN grafts into animals with disrupted circadian biology were able to rescue and restore organismal rhythmicity Wiring the synchronization of all the individual peripheral clocks through the light-controlled SCN provides a number of evolutionary advantages.

Most importantly, one master regulator more accurately ensures appropriate phase alignment in the diverse organ systems. Coupling this master controller to an entrainment as continuous and as regular as light allows the organism to respond not only to daily changes but also to seasonal changes.

Moreover, one of the first functions of biological clocks may have been to provide a mechanism to taper mutation-sensitive cellular processes like genome replication during daylight exposure to UV radiation 2. However, the central importance of the SCN in whole-animal circadian control also renders it an unlikely point of therapeutic intervention for correcting outdated evolution-imposed circuitry.

Instead, restoring clock function and circadian robustness metabolisk neuronal networks may be a more beneficial pharmacological approach to address Circadoan in the central nervous system clock.

This strategy has been promising in ameliorating anxiety-like behavior Corrective pharmacological approaches could have a profound impact on societal health, given the numerous genetic variants or mutations in clock genes that have been identified in the population Cirfadian — Brown adipose tissue BAT is a major source of mammalian facultative thermogenesis metaboliwm, additional heat production above the basal metabolic rate The classic model of BAT heat production Ciecadian with an initial stimulating event, such as exposure to cold temperature that elicits brown adipose activity through blood-borne hormonal and nutrient prompts as well as direct neuronal input from the hypothalamus 86 This function is accomplished through simultaneous consumption of lipid and carbohydrate fuel sources and rerouting of the mitochondrial proton gradient through the thermogenic effector, uncoupling protein 1 The unique, energy-dissipating activity of BAT is also controlled in a circadian manner 88 rhyhtm 90 Figure 2 B by the clock components, Rev-erbα 91PER2 92and BMAL1 93 Rev-erbα levels peak while animals are sleeping and result in direct transcriptional repression of the BAT thermogenic program, including Ucp1 Whole-animal genetic deletion metaabolism Rev-erb α largely abolishes the oscillation of BAT activity and whole-animal core temperature, suggesting that clock control of brown adipose is a major driver of the circadian rhythm of body temperature.

Consistent with this model, daily increases and decreases in BAT thermogenesis, as measured by implanted telemetric thermometers, were found to precede corresponding changes in core temperature ICrcadian further underscore the potential impact and physiological relevance of BAT heat production, previous studies have demonstrated that even subtle changes in body temperature, well within the thermogenic range driven by Mstabolism, can synchronize or reset peripheral clocks 96 Clock-mediated regulation of BAT thermogenic function also exemplifies the integral association between circadian rhythm and evolutionary demand.

As ancient rhyfhm underwent the transition from ectotherms to endotherms, BAT adopted a more clearly defined role and conferred a selective advantage not only to survive but also to metavolism in adverse environmental climates However, given the scarcity Circaeian food with which our ancestors were faced for thousands of years, the energy-dissipating nature of BAT would also prove highly unfavorable if left unchecked.

Metabooism activity begins increasing once animals awaken to provide the necessary thermal protection for hunting and gathering food in harsh environments. This network Circaidan even been further equipped with a fail-safe in the event that an animal is suddenly exposed to cold temperatures while sleeping.

The chief circadian BAT regulator, Rev-erbα, is rapidly and significantly reduced, thereby facilitating full induction of the thermogenic response This rhythmic mechanism of decreasing BAT activity during sleep is perfectly in line with evolutionary principles but is now more of a hindrance to metabolic health in the face of late night eating and calorie-rich, Western diets.

Targeting this brake on BAT function could provide a way to increase the daily BAT consumption of glucose and fat stores in a safer and more specific manner than through the more classic, ubiquitous pathway of adrenergic signaling. Furthermore, preventing the BAT clock from actively suppressing calorie-burning at night could potentially increase BAT output without an uncomfortable or dangerous elevation in body temperature that is perhaps more likely with strategies that enhance BAT activity beyond its endogenous maximal capacity.

However, whether or not the difference in energy balance from unlocking the circadian inhibition of BAT would be significant enough to mitigate the effects metabolidm metabolic Circaeian is as yet undetermined Given that the circadian rhythm of BAT function is also correlated with food intake and BAT is believed to be a contributor to diet-induced thermogenesis 99further experiments must also be carried out to tease apart the mechanistic contributions from central and dietary control of the oscillation of BAT activity.

The body's chief reservoir for diet-derived energy is Circsdian adipose tissue, which accumulates triglycerides. During periods of fasting, white adipose mobilizes these lipid stores for use as oxidative substrates in peripheral tissue such as skeletal muscle.

In this manner, evolution has programmed the circadian clock to increase lipolytic pathways during sleep to compensate for the absence of dietary energy sources in mouseand human Conversely, while animals are awake and feeding, white adipose builds up triglyceride stores with liver-produced lipid Figure 2 C.

Circadian control of lipid mobilization is mediated, at least in part, through CLOCK and BMAL1-induced rhythm of adipose triglyceride lipase Atgl and hormone sensitive lipase Hsl gene expression Indeed, genetic disruption of Bmal1 or use of the dominant negative Clock Δ 19 10mutant results in arrhythmic levels of serum free fatty acids and decreased lipolysis rates, which contributes to the development of obesity.

Additionally, adipose-specific Metqbolism deletion also seems to influence adipose-hypothalamic cross talk through alterations in the level of polyunsaturated lipid species that are released into thythm blood The repressing arm of the clock modulates lipid metabolism through PER2-dependent suppression of the highly adipogenic and insulin-sensitizing nuclear receptor Ciircadian proliferator-activated receptor-γ and Rev-erbα-dependent transcriptional repression of lipoprotein lipase Adipose tissue metabokism also a key contributor to endocrine signaling through metabolsm production of adipokines, including leptinresistinand adiponectinwhose circulating levels are robustly circadian ,
: Circadian rhythm metabolism

Circadian rhythms, sleep, and metabolism

Neuroscience : — Saper CB , Lu J , Chou TC , Gooley J The hypothalamic integrator for circadian rhythms. Trends Neurosci 28 : — Saper CB , Scammell TE , Lu J Hypothalamic regulation of sleep and circadian rhythms.

Yi CX , van der Vliet J , Dai J , Yin G , Ru L , Buijs RM Ventromedial arcuate nucleus communicates peripheral metabolic information to the suprachiasmatic nucleus.

Endocrinology : — Chou TC , Scammell TE , Gooley JJ , Gaus SE , Saper CB , Lu J Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. Lu J , Zhang YH , Chou TC , Gaus SE , Elmquist JK , Shiromani P , Saper CB Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep-wake cycle and temperature regulation.

J Neurosci 21 : — Ramsey KM , Marcheva B , Kohsaka A , Bass J The clockwork of metabolism. Annu Rev Nutr 27 : — 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 : — Buijs RM , Scheer FA , Kreier F , Yi C , Bos N , Goncharuk VD , Kalsbeek A Organization of circadian functions: interaction with the body. Prog Brain Res : — Roland BL , Sawchenko PE Local origins of some GABAergic projections to the paraventricular and supraoptic nuclei of the hypothalamus in the rat.

J Comp Neurol : — Shekhar A , Katner JS Dorsomedial hypothalamic GABA regulates anxiety in the social interaction test. Pharmacol Biochem Behav 50 : — Gamble KL , Allen GC , Zhou T , McMahon DG Gastrin-releasing peptide mediates light-like resetting of the suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation.

J Neurosci 27 : — Akanmu MA , Ukponmwan OE , Katayama Y , Honda K Neuropeptide-Y Y2-receptor agonist, PYY3—36 promotes non-rapid eye movement sleep in rat. Neurosci Res 54 : — Proc Soc Exp Biol Med 77 : — Fan W , Boston BA , Kesterson RA , Hruby VJ , Cone RD Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.

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 : — Adan RA , Cone RD , Burbach JP , Gispen WH Differential effects of melanocortin peptides on neural melanocortin receptors.

Mol Pharmacol 46 : — Cone RD Anatomy and regulation of the central melanocortin system. Nat Neurosci 8 : — Krude H , Biebermann H , Luck W , Horn R , Brabant G , Grüters A Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.

Nat Genet 19 : — Yeo GS , Farooqi IS , Aminian S , Halsall DJ , Stanhope RG , O'Rahilly S A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20 : — Vaisse C , Clement K , Guy-Grand B , Froguel P A frameshift mutation in human MC4R is associated with a dominant form of obesity.

Hinney A , Schmidt A , Nottebom K , Heibült O , Becker I , Ziegler A , Gerber G , Sina M , Görg T , Mayer H , Siegfried W , Fichter M , Remschmidt H , Hebebrand J Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans.

J Clin Endocrinol Metab 84 : — Farooqi IS , Yeo GS , Keogh JM , Aminian S , Jebb SA , Butler G , Cheetham T , O'Rahilly S Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest : — Vaisse C , Clement K , Durand E , Hercberg S , Guy-Grand B , Froguel P Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.

Ollmann MM , Wilson BD , Yang YK , Kerns JA , Chen Y , Gantz I , Barsh GS Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Quillan JM , Sadée W , Wei ET , Jimenez C , Ji L , Chang JK A synthetic human Agouti-related protein- 83— -NH2 fragment is a potent inhibitor of melanocortin receptor function.

FEBS Lett : 59 — Rossi M , Kim MS , Morgan DG , Small CJ , Edwards CM , Sunter D , Abusnana S , Goldstone AP , Russell SH , Stanley SA , Smith DM , Yagaloff K , Ghatei MA , Bloom SR A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of α-melanocyte stimulating hormone in vivo.

Baskin DG , Breininger JF , Schwartz MW Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus.

Diabetes 48 : — Elias CF , Aschkenasi C , Lee C , Kelly J , Ahima RS , Bjorbaek C , Flier JS , Saper CB , Elmquist JK Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23 : — Elias CF , Kelly JF , Lee CE , Ahima RS , Drucker DJ , Saper CB , Elmquist JK Chemical characterization of leptin-activated neurons in the rat brain.

Marsh DJ , Miura GI , Yagaloff KA , Schwartz MW , Barsh GS , Palmiter RD Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues. Brain Res : 66 — Stephens TW , Basinski M , Bristow PK , Bue-Valleskey JM , Burgett SG , Craft L , Hale J , Hoffmann J , Hsiung HM , Kriauciunas A , MacKellar W , Rosteck Jr PR , Schoner B , Smith D , Tinsley FC , Zhang XY , Heiman M The role of neuropeptide Y in the antiobesity action of the obese gene product.

Guan XM , Hess JF , Yu H , Hey PJ , van der Ploeg LH Differential expression of mRNA for leptin receptor isoforms in the rat brain. Mol Cell Endocrinol : 1 — 7.

Zigman JM , Jones JE , Lee CE , Saper CB , Elmquist JK Expression of ghrelin receptor mRNA in the rat and the mouse brain. Yi CX , Challet E , Pévet P , Kalsbeek A , Escobar C , Buijs RM A circulating ghrelin mimetic attenuates light-induced phase delay of mice and light-induced Fos expression in the suprachiasmatic nucleus of rats.

Eur J Neurosci 27 : — Yannielli PC , Molyneux PC , Harrington ME , Golombek DA Ghrelin effects on the circadian system of mice. Kalra SP , Dube MG , Pu S , Xu B , Horvath TL , Kalra PS Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20 : 68 — Prog Neurobiol 74 : 59 — Challet E Minireview: entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals.

Sakkou M , Wiedmer P , Anlag K , Hamm A , Seuntjens E , Ettwiller L , Tschöp MH , Treier M A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. Cell Metab 5 : — Cowley MA , Smart JL , Rubinstein M , Cerdán MG , Diano S , Horvath TL , Cone RD , Low MJ Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.

Elmquist JK , Ahima RS , Elias CF , Flier JS , Saper CB Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci USA 95 : — Elmquist JK , Elias CF , Saper CB From lesions to leptin: hypothalamic control of food intake and body weight.

Neuron 22 : — Flier JS , Maratos-Flier E Obesity and the hypothalamus: novel peptides for new pathways. Cell 92 : — Friedman JM , Halaas JL Leptin and the regulation of body weight in mammals. Schwartz MW , Woods SC , Porte Jr D , Seeley RJ , Baskin DG Central nervous system control of food intake.

Shimada M , Tritos NA , Lowell BB , Flier JS , Maratos-Flier E Mice lacking melanin-concentrating hormone are hypophagic and lean.

Sutcliffe JG , de Lecea L The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 62 : — Willie JT , Chemelli RM , Sinton CM , Yanagisawa M To eat or to sleep?

Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24 : — 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.

Trends Endocrinol Metab 11 : — Lin L , Faraco J , Li R , Kadotani H , Rogers W , Lin X , Qiu X , de Jong PJ , Nishino S , Mignot E The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin orexin receptor 2 gene. Cell 98 : — Hara J , Beuckmann CT , Nambu T , Willie JT , Chemelli RM , Sinton CM , Sugiyama F , Yagami K , Goto K , Yanagisawa M , Sakurai T Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.

Neuron 30 : — Nishino S , Mignot E Article reviewed: Plasma orexin-A is lower in patients with narcolepsy. Sleep Med 3 : — Peptides 27 : — La Fleur SE , Kalsbeek A , Wortel J , Buijs RM A suprachiasmatic nucleus generated rhythm in basal glucose concentrations.

J Neuroendocrinol 11 : — Ruiter M , La Fleur SE , van Heijningen C , van der Vliet J , Kalsbeek A , Buijs RM The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes 52 : — Ando H , Yanagihara H , Hayashi Y , Obi Y , Tsuruoka S , Takamura T , Kaneko S , Fujimura A Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue.

De Boer SF , Van der Gugten J Daily variations in plasma noradrenaline, adrenaline and corticosterone concentrations in rats. Physiol Behav 40 : — Ahima RS , Prabakaran D , Flier JS Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding.

Implications for energy homeostasis and neuroendocrine function. Bodosi B , Gardi J , Hajdu I , Szentirmai E , Obal Jr F , Krueger JM Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am J Physiol Regul Integr Comp Physiol : R — R Kalra SP , Bagnasco M , Otukonyong EE , Dube MG , Kalra PS Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity.

Regul Pept : 1 — Kalsbeek A , Fliers E , Romijn JA , La Fleur SE , Wortel J , Bakker O , Endert E , Buijs RM The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels. Shen J , Tanida M , Niijima A , Nagai K In vivo effects of leptin on autonomic nerve activity and lipolysis in rats.

Neurosci Lett : — Froy O The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol 28 : 61 — Green CB , Takahashi JS , Bass J The meter of metabolism.

Hirota T , Fukada Y Resetting mechanism of central and peripheral circadian clocks in mammals. Zoolog Sci 21 : — Kohsaka A , Bass J A sense of time: how molecular clocks organize metabolism.

Trends Endocrinol Metab 18 : 4 — La Fleur SE Daily rhythms in glucose metabolism: suprachiasmatic nucleus output to peripheral tissue. J Neuroendocrinol 15 : — Davidson AJ , Castañón-Cervantes O , Stephan FK Daily oscillations in liver function: diurnal vs circadian rhythmicity.

Liver Int 24 : — Froy O Cytochrome p and the biological clock in mammals. Curr Drug Metab 10 : — Frederiks WM , Marx F , Bosch KS Diurnal variation in glycogen phosphorylase activity in rat liver.

A quantitative histochemical study. Eur J Cell Biol 43 : — Ximenes da Silva A , Gendrot G , Servière J , Lavialle M Daily changes of cytochrome oxidase activity within the suprachiasmatic nucleus of the Syrian hamster.

Rivera-Coll A , Fuentes-Arderiu X , Díez-Noguera A Circadian rhythms of serum concentrations of 12 enzymes of clinical interest. Chronobiol Int 10 : — Fukuda H , Iritani N Diurnal variations of lipogenic enzyme mRNA quantities in rat liver.

Biochim Biophys Acta : — 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 : — Cailotto C , La Fleur SE , Van Heijningen C , Wortel J , Kalsbeek A , Feenstra M , Pévet P , Buijs RM The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved?

Eur J Neurosci 22 : — Kalsbeek A , Ruiter M , La Fleur SE , Cailotto C , Kreier F , Buijs RM The hypothalamic clock and its control of glucose homeostasis.

Yamazaki S , Ishida Y , Inouye S Circadian rhythms of adenosine triphosphate contents in the suprachiasmatic nucleus, anterior hypothalamic area and caudate putamen of the rat—negative correlation with electrical activity. Brain Res : — 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.

Stephan FK , Davidson AJ Glucose, but not fat, phase shifts the feeding-entrained circadian clock. Physiol Behav 65 : — Young ME , Wilson CR , Razeghi P , Guthrie PH , Taegtmeyer H Alterations of the circadian clock in the heart by streptozotocin-induced diabetes.

J Mol Cell Cardiol 34 : — Hirota T , Okano T , Kokame K , Shirotani-Ikejima H , Miyata T , Fukada Y Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts.

Iwanaga H , Yano M , Miki H , Okada K , Azama T , Takiguchi S , Fujiwara Y , Yasuda T , Nakayama M , Kobayashi M , Oishi K , Ishida N , Nagai K , Monden M Per2 gene expressions in the suprachiasmatic nucleus and liver differentially respond to nutrition factors in rats.

JPEN J Parenter Enteral Nutr 29 : — Mohri T , Emoto N , Nonaka H , Fukuya H , Yagita K , Okamura H , Yokoyama M Alterations of circadian expressions of clock genes in Dahl salt-sensitive rats fed a high-salt diet. Hypertension 42 : — Waddington Lamont E , Harbour VL , Barry-Shaw J , Renteria Diaz L , Robinson B , Stewart J , Amir S Restricted access to food, but not sucrose, saccharine, or salt, synchronizes the expression of Period2 protein in the limbic forebrain.

Chen CP , Kuhn P , Advis JP , Sarkar DK Chronic ethanol consumption impairs the circadian rhythm of pro-opiomelanocortin and period genes mRNA expression in the hypothalamus of the male rat. J Neurochem 88 : — Alcohol Clin Exp Res 29 : — Antle MC , Steen NM , Mistlberger RE Adenosine and caffeine modulate circadian rhythms in the Syrian hamster.

Neuroreport 12 : — Langlais PJ , Hall T Thiamine deficiency-induced disruptions in the diurnal rhythm and regulation of body temperature in the rat.

Metab Brain Dis 13 : — Bennett MR , Schwartz WJ Altered circadian rhythmicity is an early sign of murine dietary thiamine deficiency. J Neurol Sci : 6 — McNamara P , Seo SB , Rudic RD , Sehgal A , Chakravarti D , FitzGerald GA Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock.

Biochem Biophys Res Commun : — Balsalobre A , Marcacci L , Schibler U Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr Biol 10 : — Balsalobre A , Brown SA , Marcacci L , Tronche F , Kellendonk C , Reichardt HM , Schütz G , Schibler U Resetting of circadian time in peripheral tissues by glucocorticoid signaling.

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 : — Fu L , Patel MS , Bradley A , Wagner EF , Karsenty G The molecular clock mediates leptin-regulated bone formation. Rutter J , Reick M , Wu LC , McKnight SL Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.

Rutter J , Reick M , McKnight SL Metabolism and the control of circadian rhythms. Annu Rev Biochem 71 : — Vieira E , Nilsson EC , Nerstedt A , Ormestad M , Long YC , Garcia-Roves PM , Zierath JR , Mahlapuu M Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle.

Martin TL , Alquier T , Asakura K , Furukawa N , Preitner F , Kahn BB Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. Blander G , Guarente L The Sir2 family of protein deacetylases.

Annu Rev Biochem 73 : — Ann Med 39 : — 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.

Hirayama J , Sahar S , Grimaldi B , Tamaru T , Takamatsu K , Nakahata Y , Sassone-Corsi P CLOCK-mediated acetylation of BMAL1 controls circadian function. Belden WJ , Dunlap JC SIRT1 is a circadian deacetylase for core clock components.

J Biol Rhythms 17 : — Cassone VM , Stephan FK Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight. Nutrition 18 : — Honma KI , Honma S , Hiroshige T Critical role of food amount for prefeeding corticosterone peak in rats.

Grasl-Kraupp B , Bursch W , Ruttkay-Nedecky B , Wagner A , Lauer B , Schulte-Hermann R Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver.

Proc Natl Acad Sci USA 91 : — Saito M , Murakami E , Suda M Circadian rhythms in disaccharidases of rat small intestine and its relation to food intake.

Comperatore CA , Stephan FK Entrainment of duodenal activity to periodic feeding. J Biol Rhythms 2 : — Stephan FK , Swann JM , Sisk CL Anticipation of hr feeding schedules in rats with lesions of the suprachiasmatic nucleus.

Behav Neural Biol 25 : — Mistlberger RE Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 18 : — Hara R , Wan K , Wakamatsu H , Aida R , Moriya T , Akiyama M , Shibata S Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus.

Genes Cells 6 : — Oishi K , Miyazaki K , Ishida N Functional CLOCK is not involved in the entrainment of peripheral clocks to the restricted feeding: entrainable expression of mPer2 and Bmal1 mRNAs in the heart of Clock mutant mice on Jcl:ICR background.

Horikawa K , Minami Y , Iijima M , Akiyama M , Shibata S Rapid damping of food-entrained circadian rhythm of clock gene expression in clock-defective peripheral tissues under fasting conditions.

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 : — Stokkan KA , Yamazaki S , Tei H , Sakaki Y , Menaker M Entrainment of the circadian clock in the liver by feeding.

Lin JD , Liu C , Li S Integration of energy metabolism and the mammalian clock. Cell Cycle 7 : — Boulamery-Velly A , Simon N , Vidal J , Mouchet J , Bruguerolle B Effects of three-hour restricted food access during the light period on circadian rhythms of temperature, locomotor activity, and heart rate in rats.

Chronobiol Int 22 : — Hirao J , Arakawa S , Watanabe K , Ito K , Furukawa T Effects of restricted feeding on daily fluctuations of hepatic functions including p monooxygenase activities in rats. Mieda M , Williams SC , Richardson JA , Tanaka K , Yanagisawa M The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker.

Gooley JJ , Schomer A , Saper CB The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Landry GJ , Simon MM , Webb IC , Mistlberger RE Persistence of a behavioral food-anticipatory circadian rhythm following dorsomedial hypothalamic ablation in rats.

Landry GJ , Yamakawa GR , Webb IC , Mear RJ , Mistlberger RE The dorsomedial hypothalamic nucleus is not necessary for the expression of circadian food-anticipatory activity in rats.

J Biol Rhythms 22 : — Davidson AJ , Cappendijk SL , Stephan FK Feeding-entrained circadian rhythms are attenuated by lesions of the parabrachial region in rats. Mistlberger RE , Mumby DG The limbic system and food-anticipatory circadian rhythms in the rat: ablation and dopamine blocking studies.

Behav Brain Res 47 : — Mendoza J , Angeles-Castellanos M , Escobar C Differential role of the accumbens Shell and Core subterritories in food-entrained rhythms of rats. Behav Brain Res : — Davidson AJ Search for the feeding-entrainable circadian oscillator: a complex proposition.

Comperatore CA , Stephan FK Effects of vagotomy on entrainment of activity rhythms to food access. Physiol Behav 47 : — Mistlberger RE , Marchant EG Enhanced food-anticipatory circadian rhythms in the genetically obese Zucker rat.

Physiol Behav 66 : — Am J Physiol Regul Integr Comp Physiol : R57 — R Pendergast JS , Nakamura W , Friday RC , Hatanaka F , Takumi T , Yamazaki S Robust food anticipatory activity in BMAL1-deficient mice. PLoS ONE 4 : e Storch KF , Weitz CJ Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock.

Feillet CA , Ripperger JA , Magnone MC , Dulloo A , Albrecht U , Challet E Lack of food anticipation in Per2 mutant mice. Mistlberger RE Circadian rhythms: perturbing a food-entrained clock. Curr Biol 16 : R — R Masoro EJ , Shimokawa I , Higami Y , McMahan CA , Yu BP Temporal pattern food intake not a factor in the retardation of aging processes by dietary restriction.

J Gerontol A Biol Sci Med Sci 50A : B48 — B Koubova J , Guarente L How does calorie restriction work? Genes Dev 17 : — Masoro EJ Overview of caloric restriction and ageing. Mech Ageing Dev : — Weindruch R , Sohal RS Seminars in medicine of the Beth Israel Deaconess Medical Center.

Caloric intake and aging. N Engl J Med : — Roth GS , Lane MA , Ingram DK , Mattison JA , Elahi D , Tobin JD , Muller D , Metter EJ Biomarkers of caloric restriction may predict longevity in humans. Science : Roth GS , Mattison JA , Ottinger MA , Chachich ME , Lane MA , Ingram DK Aging in rhesus monkeys: relevance to human health interventions.

Challet E , Solberg LC , Turek FW Entrainment in calorie-restricted mice: conflicting zeitgebers and free-running conditions. Challet E , Caldelas I , Graff C , Pévet P Synchronization of the molecular clockwork by light- and food-related cues in mammals. J Neurosci 25 : — Resuehr D , Olcese J Caloric restriction and melatonin substitution: effects on murine circadian parameters.

Froy O , Miskin R The interrelations among feeding, circadian rhythms and ageing. Prog Neurobiol 82 : — Anson RM , Guo Z , de Cabo R , Iyun T , Rios M , Hagepanos A , Ingram DK , Lane MA , Mattson MP Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.

Descamps O , Riondel J , Ducros V , Roussel AM Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Goodrick CL , Ingram DK , Reynolds MA , Freeman JR , Cider N Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age.

Mech Ageing Dev 55 : 69 — Contestabile A , Ciani E , Contestabile A Dietary restriction differentially protects from neurodegeneration in animal models of excitotoxicity. Mattson MP Energy intake, meal frequency, and health: a neurobiological perspective.

Annu Rev Nutr 25 : — Sharma S , Kaur G Neuroprotective potential of dietary restriction against kainate-induced excitotoxicity in adult male Wistar rats. Brain Res Bull 67 : — Ahmet I , Wan R , Mattson MP , Lakatta EG , Talan M Cardioprotection by intermittent fasting in rats.

Circulation : — Mager DE , Wan R , Brown M , Cheng A , Wareski P , Abernethy DR , Mattson MP Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J 20 : — Mattson MP , Duan W , Wan R , Guo Z Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations.

NeuroRx 1 : — Mattson MP Dietary factors, hormesis and health. Ageing Res Rev 7 : 43 — Froy O , Chapnik N , Miskin R Effect of intermittent fasting on circadian rhythms in mice depends on feeding time. Bamshad M , Aoki VT , Adkison MG , Warren WS , Bartness TJ Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue.

Bartness TJ , Bamshad M Innervation of mammalian white adipose tissue: implications for the regulation of total body fat. Cantu RC , Goodman HM Effects of denervation and fasting on white adipose tissue.

Am J Physiol : — Youngstrom TG , Bartness TJ White adipose tissue sympathetic nervous system denervation increases fat pad mass and fat cell number.

Kreier F , Fliers E , Voshol PJ , Van Eden CG , Havekes LM , Kalsbeek A , Van Heijningen CL , Sluiter AA , Mettenleiter TC , Romijn JA , Sauerwein HP , Buijs RM Selective parasympathetic innervation of subcutaneous and intra-abdominal fat—functional implications.

Zvonic S , Floyd ZE , Mynatt RL , Gimble JM Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Obesity Silver Spring 15 : — Loboda A , Kraft WK , Fine B , Joseph J , Nebozhyn M , Zhang C , He Y , Yang X , Wright C , Morris M , Chalikonda I , Ferguson M , Emilsson V , Leonardson A , Lamb J , Dai H , Schadt E , Greenberg HE , Lum PY Diurnal variation of the human adipose transcriptome and the link to metabolic disease.

BMC Med Genomics 2 : 7. Suzuki M , Shimomura Y , Satoh Y Diurnal changes in lipolytic activity of isolated fat cells and their increased responsiveness to epinephrine and theophylline with meal feeding in rats.

J Nutr Sci Vitaminol Tokyo 29 : — Saad MF , Riad-Gabriel MG , Khan A , Sharma A , Michael R , Jinagouda SD , Boyadjian R , Steil GM Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab 83 : — 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 : — Bray MS , Young ME Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes Rev 8 : — 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.

Oishi K , Shirai H , Ishida N CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor α PPARα in mice. Biochem J : — J Atheroscler Thromb 12 : — Canaple L , Rambaud J , Dkhissi-Benyahya O , Rayet B , Tan NS , Michalik L , Delaunay F , Wahli W , Laudet V Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor α defines a novel positive feedback loop in the rodent liver circadian clock.

Mol Endocrinol 20 : — Wang N , Yang G , Jia Z , Zhang H , Aoyagi T , Soodvilai S , Symons JD , Schnermann JB , Gonzalez FJ , Litwin SE , Yang T Vascular PPARγ controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab 8 : — Chawla A , Lazar MA Induction of Rev-ErbA α, an orphan receptor encoded on the opposite strand of the α-thyroid hormone receptor gene, during adipocyte differentiation.

Torra IP , Tsibulsky V , Delaunay F , Saladin R , Laudet V , Fruchart JC , Kosykh V , Staels B Circadian and glucocorticoid regulation of Rev-erb α expression in liver.

Fontaine C , Dubois G , Duguay Y , Helledie T , Vu-Dac N , Gervois P , Soncin F , Mandrup S , Fruchart JC , Fruchart-Najib J , Staels B The orphan nuclear receptor Rev-Erbα is a peroxisome proliferator-activated receptor PPAR γ target gene and promotes PPARγ-induced adipocyte differentiation. Duez H , Staels B Rev-erb α gives a time cue to metabolism.

FEBS Lett : 19 — Lau P , Nixon SJ , Parton RG , Muscat GE RORα regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. Akashi M , Takumi T The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1.

Nat Struct Mol Biol 12 : — Ueda HR , Chen W , Adachi A , Wakamatsu H , Hayashi S , Takasugi T , Nagano M , Nakahama K , Suzuki Y , Sugano S , Iino M , Shigeyoshi Y , Hashimoto S A transcription factor response element for gene expression during circadian night. Liu C , Li S , Liu T , Borjigin J , Lin JD Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism.

Grimaldi B , Sassone-Corsi P Circadian rhythms: metabolic clockwork. Yanagihara H , Ando H , Hayashi Y , Obi Y , Fujimura A High-fat feeding exerts minimal effects on rhythmic mRNA expression of clock genes in mouse peripheral tissues.

Chronobiol Int 23 : — Satoh Y , Kawai H , Kudo N , Kawashima Y , Mitsumoto A Time-restricted feeding entrains daily rhythms of energy metabolism in mice. Kohsaka A , Laposky AD , Ramsey KM , Estrada C , Joshu C , Kobayashi Y , Turek FW , Bass J High-fat diet disrupts behavioral and molecular circadian rhythms in mice.

Cell Metab 6 : — Is it necessary to fast as long as 18 h or are 11—12 h sufficient 68? The answer almost certainly depends on baseline metabolic health and the extent of the desired change in weight and metabolic parameters.

The circadian expression of the core clock and the genes under its regulation is found not only in the master clock i.

Peripheral clocks respond not only to the synchronizing cues emanating from the light-entrained master clock but also to rhythms in feeding and fasting.

Furthermore, different peripheral tissues have varying degrees of responses to food intake during the inactive phase, thus potentiating peripheral misalignment.

Obesogenic diets also disrupt feeding rhythms and thereby circadian metabolism. In modern humans, the discordance between behavioral and endogenous clock rhythms is prevalent, and this temporal misalignment leads to systemic metabolic dysregulation.

While evening light exposure will likely continue to be a reality, food intake is a powerful zeitgeber around which behaviors are more plastic. Active phase TRF may have remarkable potential to prevent the deleterious metabolic effects of both obesogenic diets and night shift work.

The relative importance of the core molecular clock as a mediator of food intake signals remains to be delineated. The answers to these questions could be important in developing potential pharmacological interventions e. Other lifestyle interventions that could influence circadian metabolism and prevent its misalignment are also being examined.

Exercise in particular may influence peripheral clocks in skeletal muscles and adipose tissue as it activates many of the same pathways as fasting does, and these feed back into the core clock Indeed, acute exercise was found to alter the human subcutaneous adipose tissue transcriptome Recently, a human phase response curve for exercise was created Phase response curves illustrate the relationship between the time of zeitgeber exposure and the resultant phase shifts advances or delays of the clock.

A phase response curve for food intake will likewise be an essential tool for understanding how to prevent or alleviate circadian misalignment by TRF. Accessing the nutrient-responsive peripheral circadian system in humans remains challenging, and innovative methods are required to translate the large body of mechanistic work in animals.

Serial sampling is necessary to observe h rhythms, which presents the particular challenge for invasive studies e. Nevertheless, because animal studies have shown that the circadian metabolome and its response to nutrition are highly tissue-specific , , this work is highly important.

Circadian transcriptomics and metabolomics studies in humans have been carried out using serial samples of plasma, muscle biopsies, and subcutaneous adipose tissue. However, further studies are needed to synthesize these large datasets toward identification of biomarkers of circadian metabolic function.

Indeed, preliminary efforts are underway to identify human circadian biomarkers If they are sufficiently well-defined, these biomarkers could be screened at their peaks and nadirs to determine interpretable signatures of circadian alignment and identify early markers of circadian disruption in metabolic pathophysiology.

Alternatives to plasma for non-invasive serial sampling include urine and breath. The latter was used in circadian metabolomics in a proof-of-principle study , and it has recently been highlighted as an ideal method for continuous sampling and rapid untargeted metabolomic analysis , making this an exciting avenue for translational work.

A key challenge in the translational application of circadian biology is the large interindividual variations in metabolite rhythms 92 , , What causes these variations, and how are they related to health outcomes?

In some cases, variability may be associated with chronotype The interindividual differences in the circadian metabolic response to misaligned zeitgebers, especially in the context of shift work, warrant further attention. Moreover, the response of the human circadian metabolome under various diet conditions deserves further exploration given the largescale alterations observed in mice At the same time, future research in animal models may elucidate the circadian effects of specific macronutrient ratios, micronutrients and supplements [e.

Together this will inform novel therapeutic approaches to combat metabolic disease in the modern environment. This work was funded by grants from the Natural Sciences and Engineering Research Council NSERC, RGPIN of Canada, the New Investigator Grant of Banting and Best Diabetes Centre BBDC , and the Canadian Institutes of Health Research CIHR, PJT to H-KS.

LP was a recipient of the Charles Hollenberg Summer Studentship awarded by the Banting and Best Diabetes Centre BBDC at the University of Toronto. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Wang Z , Klipfell E , Bennett BJ , et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Turnbaugh PJ , Ley RE , Mahowald MA , Magrini V , Mardis ER , Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest.

Mukherji A , Kobiita A , Ye T , Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Thaiss CA , Zeevi D , Levy M , et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis.

Zarrinpar A , Chaix A , Yooseph S , Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome.

Voigt RM , Forsyth CB , Green SJ , et al. Circadian disorganization alters intestinal microbiota. Cani PD , Delzenne NM.

The gut microbiome as therapeutic target. Pharmacol Ther. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. Solt LA , Wang Y , Banerjee S , et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.

Hirota T , Lee JW , Lewis WG , et al. High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. Maier B , Wendt S , Vanselow JT , et al. A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock.

Zhang EE , Liu AC , Hirota T , et al. A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Zhang R , Lahens NF , Ballance HI , Hughes ME , Hogenesch JB.

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I Introduction

Yang S, Liu A, Weidenhammer A, Cooksey RC, McClain D, Kim MK, Aguilera G, Abel ED, Chung JH. The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology ; : — Zhao Y, Zhang Y, Zhou M, Wang S, Hua Z, Zhang J.

Loss of mPer2 increases plasma insulin levels by enhanced glucose-stimulated insulin secretion and impaired insulin clearance in mice. FEBS Lett ; : — CAS PubMed Google Scholar. Griebel G, Ravinet-Trillou C, Beeske S, Avenet P, Pichat P.

Front Endocrinol Lausanne ; 5 : Google Scholar. Lamia KA, Papp SJ, Yu RT, Barish GD, Uhlenhaut NH, Jonker JW, Downes M, Evans RM. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.

Delezie J, Dumont S, Dardente H, Oudart H, Grechez-Cassiau A, Klosen P, Teboul M, Delaunay F, Pevet P, Challet E. The nuclear receptor REV-ERBalpha is required for the daily balance of carbohydrate and lipid metabolism.

FASEB J ; 26 : — Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, Jager J, Lazar MA. Rev-erbalpha and Rev-erbbeta coordinately protect the circadian clock and normal metabolic function.

Genes Dev ; 26 : — 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. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo SH, Takahashi JS, Butler AA, Kamenecka TM, Burris TP. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists.

Nature ; : 62— Woldt E, Sebti Y, Solt LA, Duhem C, Lancel S, Eeckhoute J, Hesselink MK, Paquet C, Delhaye S, Shin Y, Kamenecka TM, Schaart G, Lefebvre P, Neviere R, Burris TP, Schrauwen P, Staels B, Duez H. Rev-erb-alpha modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.

Nat Med ; 19 : — Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z, Feng D, Armour SM, Remsberg JR, Jager J, Soccio RE, Steger DJ, Lazar MA. Discrete functions of nuclear receptor Rev-erbalpha couple metabolism to the clock.

Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C, Kobayashi Y, Turek FW, Bass J. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab ; 6 : — Yamamoto H, Nagai K, Nakagawa H. Role of SCN in daily rhythms of plasma glucose, FFA, insulin and glucagon.

Chronobiol Int ; 4 : — Van den Pol AN, Powley T. A fine-grained anatomical analysis of the role of the rat suprachiasmatic nucleus in circadian rhythms of feeding and drinking.

Brain Res ; : — Coomans CP, van den Berg SA, Lucassen EA, Houben T, Pronk AC, van der Spek RD, Kalsbeek A, Biermasz NR, Willems van Dijk K, Romijn JA, Meijer JH.

The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Mendoza J, Pevet P, Challet E. High-fat feeding alters the clock synchronization to light. J Physiol ; : — Paschos GK, Ibrahim S, Song WL, Kunieda T, Grant G, Reyes TM, Bradfield CA, Vaughan CH, Eiden M, Masoodi M, Griffin JL, Wang F, Lawson JA, Fitzgerald GA.

Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nat Med ; 18 : — Zvonic S, Ptitsyn AA, Conrad SA, Scott LK, Floyd ZE, Kilroy G, Wu X, Goh BC, Mynatt RL, Gimble JM.

Characterization of peripheral circadian clocks in adipose tissues. Diabetes ; 55 : — Gomez-Abellan P, Hernandez-Morante JJ, Lujan JA, Madrid JA, Garaulet M. Clock genes are implicated in the human metabolic syndrome. Int J Obes Lond ; 32 : — CAS Google Scholar.

Ando H, Yanagihara H, Hayashi Y, Obi Y, Tsuruoka S, Takamura T, Kaneko S, Fujimura A. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue.

Otway DT, Mantele S, Bretschneider S, Wright J, Trayhurn P, Skene DJ, Robertson MD, Johnston JD. Rhythmic diurnal gene expression in human adipose tissue from individuals who are lean, overweight, and type 2 diabetic.

Diabetes ; 60 : — Prasai MJ, Mughal RS, Wheatcroft SB, Kearney MT, Grant PJ, Scott EM. Diurnal variation in vascular and metabolic function in diet-induced obesity: divergence of insulin resistance and loss of clock rhythm.

Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, Maruyama S, Walsh K. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest ; : — Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J.

Brown adipose tissue activity controls triglyceride clearance. Nat Med ; 17 : — Nam D, Guo B, Chatterjee S, Chen MH, Nelson D, Yechoor VK, Ma K. The adipocyte clock controls brown adipogenesis through the TGF-beta and BMP signaling pathways. J Cell Sci ; : — Xu H, Li H, Woo SL, Kim SM, Shende VR, Neuendorff N, Guo X, Guo T, Qi T, Pei Y, Zhao Y, Hu X, Zhao J, Chen L, Chen L, Ji JY, Alaniz RC, Earnest DJ, Wu C.

Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance. J Biol Chem ; : — Sato S, Sakurai T, Ogasawara J, Takahashi M, Izawa T, Imaizumi K, Taniguchi N, Ohno H, Kizaki T.

A circadian clock gene, Rev-erbalpha, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression. J Immunol ; : — Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.

N Engl J Med ; : — Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA ; : — Ma X, Zhou Z, Chen Y, Wu Y, Liu Y. RBP4 functions as a hepatokine in the regulation of glucose metabolism by the circadian clock in mice.

Diabetologia ; 59 : — PubMed Google Scholar. Ma D, Liu T, Chang L, Rui C, Xiao Y, Li S, Hogenesch JB, Chen YE, Lin JD. 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. Nat Med ; 16 : — Rakshit K, Qian J, Colwell CS, Matveyenko AV. The islet circadian clock: entrainment mechanisms, function and role in glucose homeostasis. Diabetes Obes Metab ; 17 Suppl 1 : — Vieira E, Marroqui L, Batista TM, Caballero-Garrido E, Carneiro EM, Boschero AC, Nadal A, Quesada I.

The clock gene Rev-erbalpha regulates pancreatic beta-cell function: modulation by leptin and high-fat diet. Muhlbauer E, Wolgast S, Finckh U, Peschke D, Peschke E. Indication of circadian oscillations in the rat pancreas.

FEBS Lett ; : 91— Stamenkovic JA, Olsson AH, Nagorny CL, Malmgren S, Dekker-Nitert M, Ling C, Mulder H. Regulation of core clock genes in human islets.

Metabolism ; 61 : — Qian J, Yeh B, Rakshit K, Colwell CS, Matveyenko AV. Circadian disruption and diet-induced obesity synergize to promote development of beta cell failure and diabetes in male rats. Perelis M, Marcheva B, Ramsey KM, Schipma MJ, Hutchison AL, Taguchi A, Peek CB, Hong H, Huang W, Omura C, Allred AL, Bradfield CA, Dinner AR, Barish GD, Bass J.

Pancreatic beta cell enhancers regulate rhythmic transcription of genes controlling insulin secretion. Science ; : aac Lee J, Moulik M, Fang Z, Saha P, Zou F, Xu Y, Nelson DL, Ma K, Moore DD, Yechoor VK.

Bmal1 and beta-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced beta-cell failure in mice. Mol Cell Biol ; 33 : — Oishi K, Ohkura N, Wakabayashi M, Shirai H, Sato K, Matsuda J, Atsumi G, Ishida N.

J Thromb Haemost ; 4 : — Takeda N, Maemura K, Horie S, Oishi K, Imai Y, Harada T, Saito T, Shiga T, Amiya E, Manabe I, Ishida N, Nagai R.

Thrombomodulin is a clock-controlled gene in vascular endothelial cells. Anea CB, Zhang M, Stepp DW, Simkins GB, Reed G, Fulton DJ, Rudic RD. Vascular disease in mice with a dysfunctional circadian clock. Circulation ; : — Viswambharan H, Carvas JM, Antic V, Marecic A, Jud C, Zaugg CE, Ming XF, Montani JP, Albrecht U, Yang Z.

Mutation of the circadian clock gene Per2 alters vascular endothelial function. Kunieda T, Minamino T, Miura K, Katsuno T, Tateno K, Miyauchi H, Kaneko S, Bradfield CA, FitzGerald GA, Komuro I. Reduced nitric oxide causes age-associated impairment of circadian rhythmicity.

Circ Res ; : — Westgate EJ, Cheng Y, Reilly DF, Price TS, Walisser JA, Bradfield CA, FitzGerald GA. Genetic components of the circadian clock regulate thrombogenesis in vivo. Yokoyama M, Okada S, Nakagomi A, Moriya J, Shimizu I, Nojima A, Yoshida Y, Ichimiya H, Kamimura N, Kobayashi Y, Ohta S, Fruttiger M, Lozano G, Minamino T.

Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. Cell Rep ; 7 : — Harrison BC, Leinwand LA. Fighting fat with muscle: bulking up to slim down. Cell Metab ; 7 : 97— Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton JA, Ouchi N, LeBrasseur NK, Walsh K.

Cell Metab ; 7 : — Dyar KA, Ciciliot S, Wright LE, Bienso RS, Tagliazucchi GM, Patel VR, Forcato M, Paz MI, Gudiksen A, Solagna F, Albiero M, Moretti I, Eckel-Mahan KL, Baldi P, Sassone-Corsi P, Rizzuto R, Bicciato S, Pilegaard H, Blaauw B, Schiaffino S.

Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Mol Metab ; 3 : 29— Schroder EA, Harfmann BD, Zhang X, Srikuea R, England JH, Hodge BA, Wen Y, Riley LA, Yu Q, Christie A, Smith JD, Seward T, Horrell EM, Mula J, Peterson CA, Butterfield TA, Esser KA.

Intrinsic muscle clock is necessary for musculoskeletal health. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, Abramson L, Katz MN, Korem T, Zmora N, Kuperman Y, Biton I, Gilad S, Harmelin A, Shapiro H, Halpern Z, Segal E, Elinav E.

Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell ; : — Liang X, Bushman FD, FitzGerald GA. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock.

Kudo T, Akiyama M, Kuriyama K, Sudo M, Moriya T, Shibata S. Diabetologia ; 47 : — Eckel-Mahan KL, Patel VR, de Mateo S, Orozco-Solis R, Ceglia NJ, Sahar S, Dilag-Penilla SA, Dyar KA, Baldi P, Sassone-Corsi P. Reprogramming of the circadian clock by nutritional challenge. Scott EM, Carter AM, Grant PJ.

Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Valladares M, Obregon AM, Chaput JP.

Association between genetic variants of the clock gene and obesity and sleep duration. J Physiol Biochem ; 71 : — Dashti HS, Smith CE, Lee YC, Parnell LD, Lai CQ, Arnett DK, Ordovas JM, Garaulet M. CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American.

Chronobiol Int ; 31 : — Kovanen L, Donner K, Kaunisto M, Partonen T. CRY1, CRY2 and PRKCDBP genetic variants in metabolic syndrome. Hypertens Res ; 38 : — Leu HB, Chung CM, Lin SJ, Chiang KM, Yang HC, Ho HY, Ting CT, Lin TH, Sheu SH, Tsai WC, Chen JH, Yin WH, Chiu TY, Chen CI, Fann CS, Chen YT, Pan WH, Chen JW.

Association of circadian genes with diurnal blood pressure changes and non-dipper essential hypertension: a genetic association with young-onset hypertension.

Obayashi K, Saeki K, Tone N, Kurumatani N. Relationship between melatonin secretion and nighttime blood pressure in elderly individuals with and without antihypertensive treatment: a cross-sectional study of the HEIJO-KYO cohort. Hypertens Res ; 37 : — 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 : — Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment.

Leproult R, Holmback U, Van Cauter E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss.

Diabetes ; 63 : — Fonken LK, Lieberman RA, Weil ZM, Nelson RJ. Dim light at night exaggerates weight gain and inflammation associated with a high-fat diet in male mice. 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.

Gangwisch JE, Malaspina D, Boden-Albala B, Heymsfield SB. Inadequate sleep as a risk factor for obesity: analyses of the NHANES I.

Sleep ; 28 : — Cespedes EM, Bhupathiraju SN, Li Y, Rosner B, Redline S, Hu FB. Long-term changes in sleep duration, energy balance and risk of type 2 diabetes. Moller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R, Lo JC, Santhi N, von Schantz M, Smith CP, Dijk DJ.

Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. Proc Natl Acad Sci USA ; : E—E Reutrakul S, Van Cauter E. Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes.

Ann N Y Acad Sci ; : — Koren D, O'Sullivan KL, Mokhlesi B. Metabolic and glycemic sequelae of sleep disturbances in children and adults. Curr Diab Rep ; 15 : Adamovich Y, Aviram R, Asher G. The emerging roles of lipids in circadian control.

Biochim Biophys Acta ; : — Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.

Cell Metab ; 15 : — Asher G, Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock.

Cell ; : 84— 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 : e 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. Doi R, Oishi K, Ishida N. CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2.

Chappuis S, Ripperger JA, Schnell A, Rando G, Jud C, Wahli W, Albrecht U. Role of the circadian clock gene Per2 in adaptation to cold temperature.

Mol Metab ; 2 : — Zani F, Breasson L, Becattini B, Vukolic A, Montani JP, Albrecht U, Provenzani A, Ripperger JA, Solinas G. PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression.

Barclay JL, Shostak A, Leliavski A, Tsang AH, Johren O, Muller-Fielitz H, Landgraf D, Naujokat N, van der Horst GT, Oster H. High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice. Am J Physiol Endocrinol Metab ; : E—E Download references.

Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

You can also search for this author in PubMed Google Scholar. Correspondence to Tohru Minamino. Reprints and permissions. Shimizu, I. A role for circadian clock in metabolic disease. Hypertens Res 39 , — Download citation. Received : 06 January Revised : 17 January Accepted : 18 January Published : 18 February Issue Date : July Anyone you share the following link with will be able to read this content:.

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Skip to main content Thank you for visiting nature. nature hypertension research review series article. Download PDF. Subjects Circadian rhythms Diabetes Obesity. Abstract Many human behaviors and physiological activities show circadian rhythms.

Effects of dietary fibre on metabolic health and obesity Article 07 February Aging and aging-related diseases: from molecular mechanisms to interventions and treatments Article Open access 16 December Chronic inflammation in the etiology of disease across the life span Article 05 December Clock The mutant Clock transgene Clock Δ19 has deletion of exon 19, resulting in loss of 51 amino acids in the C-terminal of the Clock protein.

Bmal1 Although Clock and Bmal1 form a heterodimer to exert their biological effects, the metabolic profile of mice with Bmal1 depletion is not a phenocopy of that seen in Clock mutant mice. Central clock The circadian rhythm is generated in the SCN of the anterior hypothalamus.

Peripheral clocks The major roles of the peripheral clocks are orchestration of food intake and metabolic processes. Adipose tissue White adipose tissue was initially thought to be mainly involved in energy storage, but it is now widely accepted that it also has an endocrine function and secretes a variety of factors referred to as adipokines.

Liver The liver has a major role in the maintenance of systemic metabolism, as it is involved in glycogen storage, protein synthesis, hormone production and detoxification.

Blood vessels Although dietary obesity has a marked effect on clock genes in the visceral fat, liver and pancreas, clock gene cycling is well preserved in the aorta. Clock gene polymorphism and human metabolic disorders Polymorphism of the CLOCK gene was reported to have a role in the development of diabetes in humans, which is associated with a low or high prevalence of metabolic syndrome according to the haplotype.

Sleep disorders, circadian rhythm and metabolic syndrome It is well accepted that diurnal variation of physiological rhythms is important for health and disruption of the regular circadian rhythm by working night shifts or continuously rotating shifts increases the risk of developing obesity and diabetes.

Conclusions There is increasing evidence of a tight connection between metabolism and circadian rhythms, and it has been shown that metabolic stress promotes disturbance of clock-related genes in several key organs Figure 1. Figure 1.

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Crosstalk between metabolism and circadian clocks | Nature Reviews Molecular Cell Biology

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You can also search for this author in PubMed Google Scholar. Correspondence to Etienne Challet. Perelman School of Medicine, University of Pennsylvania, Pennsylania, Pennsylvania, USA.

Reprints and permissions. Grosbellet, E. Circadian Rhythms and Metabolism. In: Ahima, R. eds Metabolic Syndrome. Springer, Cham. Received : 21 February Accepted : 22 April Published : 16 June Publisher Name : Springer, Cham.

Online ISBN : eBook Packages : Springer Reference Medicine Reference Module Medicine. Policies and ethics. Skip to main content. Abstract The circadian system relies on a master clock in the suprachiasmatic nucleus of the hypothalamus SCN , synchronizing a multitude of brain and peripheral oscillators that set physiological and metabolic functions in phase with the light—dark cycle.

Keywords Circadian rhythm Clock gene Feeding time Desynchronization Metabolic disturbances Obesity Diabetes. References Abe M, Herzog ED, Yamazaki S, Straume M, Tei H, Sakaki Y, Menaker M, Block GD Circadian rhythms in isolated brain regions.

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These findings reveal the negative effect of disruption of circadian rhythms on physiology. Disruption of circadian coordination has also been found to accelerate cancer proneness and malignant growth, suggesting that the circadian clock controls tumor progression 7 — 9.

Also, chronic reversal of the external light-dark cycle at weekly intervals resulted in a significant decrease in the survival time of cardiomyopathic hamsters Circadian rhythms change with normal aging, including a shift in the phase and decrease in amplitude 11 — Indeed, longevity in hamsters is decreased with a disruption of rhythmicity and is increased in older animals given fetal suprachiasmatic implants that restore higher amplitude rhythms Thus, disruption of circadian coordination may be manifested by hormone imbalance, psychological and sleep disorders, cancer proneness, and reduced life span 3 , 7 — 10 , In contrast, resetting of circadian rhythms has led to well-being and increased longevity 14 , These findings reveal the prominent influence of the circadian clock on human physiology and pathophysiology.

In mammals, the central circadian clock is located in the suprachiasmatic nuclei SCN of the anterior hypothalamus in the brain. The SCN clock is composed of multiple, single-cell circadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms 17 — Similar clock oscillators have been found in peripheral tissues, such as the liver, intestine, heart, and retina 3 , 21 — 23 Fig.

SCN oscillation is not exactly 24 h; therefore, it is necessary to entrain the circadian pacemaker each day to the external light-dark cycle to prevent drifting or free-running out of phase. Light is the most potent synchronizer for the SCN Light is perceived by the retina, and the signal is transmitted via the retinohypothalamic tract RHT to the SCN 3 , 25 , As a result, vasoactive intestinal polypeptide, an intrinsic SCN factor, acutely activates and synchronizes SCN neurons and coordinates behavioral rhythms 27 , The SCN sends signals to peripheral oscillators to prevent the dampening of circadian rhythms in these tissues.

The SCN accomplishes this task via neuronal connections or circulating humoral factors 29 Fig. Several humoral factors expressed cyclically by the SCN, such as TGFα 30 , prokineticin 2 31 , and cardiotrophin-like cytokine 32 , have been shown to affect peripheral clocks because their intracerebroventricular injection inhibited nocturnal locomotor activity.

In turn, SCN rhythms can be altered by neuronal and endocrine inputs 33 see Section IV. Complete destruction of SCN neurons abolishes overall circadian rhythmicity in the periphery, because of loss of synchrony among individual cells and damping of the rhythm at the population level.

However, at the cellular level each cell oscillates, but with a different phase 34 , Resetting signals of the central and peripheral clocks. Light is absorbed through the retina and is transmitted to the SCN via the RHT. The SCN then dictates the entrainment of peripheral oscillators via humoral factors or autonomic innervation.

As a result, tissue-specific hormone expression and secretion and metabolic pathways exhibit circadian oscillation. In addition, the SCN dictates rhythms of locomotor activity, sleep-wake cycle, blood pressure, and body temperature.

Food and feeding regimens affect either peripheral clocks or the central clock in the SCN. In mammals, the clock is an intracellular mechanism sharing the same molecular components in SCN neurons and peripheral cells Generation of circadian rhythms is dependent on the concerted coexpression of specific clock genes.

Transcriptional-translational feedback loops lie at the very heart of the core clock mechanism. Many clock gene products function as transcription factors that possess PAS PER, ARNT, SIM and basic helix-loop-helix domains involved in protein-protein and protein-DNA interactions, respectively.

These factors ultimately activate or repress their own expression and, thus, constitute a self-sustained transcriptional feedback loop. Changes in concentration, subcellular localization, posttranslational modifications phosphorylation, acetylation, deacetylation, SUMOylation , and delays between transcription and translation lead to the approximately h cycle 2 , 3 , 40 , The genes encoding the core clock mechanisms include circadian locomotor output cycles kaput Clock , brain and muscle-Arnt-like 1 Bmal1 , Period1 Per1 , Period2 Per2 , Period3 Per3 , Cryptochrome1 Cry1 , and Cryptochrome2 C ry2.

In the mouse, the first clock gene identified encodes the transcription factor CLOCK 42 , which dimerizes with BMAL1 to activate transcription Fig. BMAL1 can also dimerize with other CLOCK homologs, such as neuronal PAS domain protein 2 NPAS2 , to activate transcription and sustain rhythmicity 43 , Thus, CLOCK:BMAL1 heterodimers bind to E-box sequences and mediate transcription of a large number of genes, including those of the negative feedback loop Per s and Cry s.

When PERs and CRYs are produced in the cytoplasm, they oligomerize and translocate to the nucleus to inhibit CLOCK:BMAL1-mediated transcription Fig. Per s and Bmal1 have robust oscillation in opposite phases correlating with their opposing functions All the aforementioned clock genes exhibit a h rhythm in SCN cells and peripheral tissues, except for Clock , which has been shown not to oscillate in the SCN Recent studies have demonstrated that CLOCK has intrinsic histone acetyltransferase activity, suggesting that rhythmic activation of chromatin remodeling may underlie the clock transcriptional network 47 , Indeed, cyclic histone acetylation and methylation have been observed on the promoters of several clock genes 48 — The core mechanism of the mammalian circadian clock and its link to energy metabolism.

The cellular oscillator is composed of a positive limb CLOCK and BMAL1 and a negative limb CRYs and PERs. CLOCK and BMAL1 dimerize in the cytoplasm and translocate to the nucleus. The CLOCK:BMAL1 heterodimer then binds to enhancer E-box sequences located in the promoter region of Per and Cry genes to activate their transcription.

After translation, PERs and CRYs undergo nuclear translocation and inhibit CLOCK:BMAL1, resulting in decreased transcription of their own genes. The autoregulatory transcription—translation loop comprising CLOCK:BMAL1 and PER—CRY constitutes the core clock and generates h rhythms of gene expression.

CLOCK:BMAL1 heterodimer also induces the transcription of Rev-erb α and Ror α. RORα and REV-ERBα regulate lipid metabolism and adipogenesis, and also participate in the regulation of Bmal1 expression. RORα stimulates and REV-ERBα inhibits Bmal1 transcription, acting through ROR elements RORE.

CLOCK:BMAL1 heterodimer also mediates the transcription of Ppar α, a nuclear receptor involved in glucose and lipid metabolism. PPARα activates transcription of Rev-erb α by binding to a PPRE. PPARα also induces Bmal1 expression, acting through PPRE located in its promoter. Several other players appear to be important to sustain clock function.

Casein kinase I epsilon CKIε is thought to phosphorylate the PER proteins and, thereby, enhance their instability and degradation 40 , 54 — CKIε also phosphorylates and partially activates the transcription factor BMAL1 Bmal1 expression is negatively regulated by the transcription factor reverse erythroblastosis virus α REV-ERBα 58 , which recruits histone deacetylase complexes Bmal1 expression is positively regulated by retinoic acid receptor-related orphan receptor α RORα and RORγ 60 via the ROR response element RORE Thus, Bmal1 oscillation is driven by a rhythmic change in RORE occupancy by RORs and REV-ERBα.

This alternating promoter occupancy occurs because REV-ERBα levels are robustly rhythmic, a result of direct transcriptional activation of the Rev-erb α gene by the heterodimer CLOCK:BMAL1 58 Fig.

These findings emphasize the circadian control over a large portion of the transcriptomes in peripheral tissues. In an elegant study, it was shown that tetracycline-responsive, hepatocyte-specific overexpression of REV-ERBα, which caused constitutive repression of Bmal1 transcription see Section III.

B when the tetracycline analog doxycycline was absent, resulted in the loss of clock function. Microarray analysis of livers after removal of doxycycline from the food revealed that the great majority of the rhythmic genes was abolished, indicating that these genes are normally driven by the local liver clock and not by rhythmic systemic signals.

Interestingly, 31 genes, among which was the core clock gene mPer2 , still exhibited robust circadian patterns of expression, suggesting that this small subset of rhythmic liver genes is driven by systemic signal independent of the liver clock Thus, for a peripheral tissue, such as the liver, signals from the central SCN clock or the local endogenous clock may control rhythmic gene expression 70 , Indeed, as mentioned in Section III.

A , peripheral rhythms persist in the periphery at the cellular level even without SCN control 34 , The SCN provides its most intense output to the subparaventricular zone SPZ and dorsomedial hypothalamus DMH 72 , SCN fibers have also been shown to terminate in and around the arcuate nucleus ARC in the ventromedial hypothalamus VMH and in the ventral part of the lateral hypothalamus, suggesting an interaction with areas involved in food intake and organization of activity 74 Fig.

The role of the SPZ and DMH in regulating circadian rhythms was determined using lesion studies 75 , Destruction of the ventral SPZ reduced circadian rhythms of sleep-wakefulness and locomotor activity but had little effect on circadian regulation of body temperature Conversely, degeneration of the dorsal SPZ disrupted circadian regulation of body temperature with minimal effect on sleep-wakefulness and locomotor activity Thus, ventral SPZ regulates sleep-wakefulness, whereas dorsal SPZ regulates body temperature Ablation of DMH cell bodies, which receive inputs from both the SCN and the SPZ, resulted in severe impairment of circadian-regulated sleep-wakefulness, locomotor activity, corticosteroid secretion, and feeding Thus, DMH and VMH constitute a gateway between the master pacemaker neurons of the SCN and cell bodies located within brain centers in the hypothalamus 77 Fig.

SCN afferents and efferents. The SCN can be entrained by light, hormones and nutrients, and neuronal connections green arrows. The SCN sends neuronal connections to the ARC, MPOA, PVN, and SPZ blue arrows.

Hormones and nutrients may affect the ARC directly. The ARC controls expression of orexins and MCH in LH. The SPZ innervates the DMH, which, in turn, innervates PVN, VLPO, and LH, regulating corticosteroid production, sleep, and feeding, respectively.

MPOA, PVN, and DMH through the autonomic nervous system regulate adipose tissue, liver, and other peripheral tissues red arrows. In turn, gut-derived hormones, nutrients, and abdominal distension signal to the brain through the autonomic nervous system.

LH, Lateral hypothalamus; ORX, orexins; Raphe, brainstem raphe nuclei; VLPO, ventrolateralpreoptic area. The ventral and dorsal borders of the PVN, the location of preautonomic nervous system neurons, are selectively innervated by fibers of the SCN The SCN can control energy homeostasis by providing its output to preautonomic neurons in the hypothalamus that are connected to the parasympathetic and sympathetic systems Studies have shown that many interneurons, which project from the SCN to the PVN, contain γ-aminobutyric acid as neurotransmitter and inhibit the PVN 80 , Thus, it seems that the SCN is capable of controlling peripheral tissues not only by the secretion of humoral signals but also by affecting the two branches of the autonomic nervous system, i.

There are two major ways by which metabolic information may reach the SCN: 1 the sympathetic and parasympathetic branches of the autonomic nervous system; and 2 hormones or nutrients, such as glucose, that cross the blood-brain barrier. From the sites where visceral sympathetic information enters the brain the dorsal horn and visceral parasympathetic information enters the brain the nucleus of the tractus solitarius , no projections are known to the SCN.

Thus, it is possible that autonomic information is transmitted first to the PVN and then to the SCN Fig. This seems to be different for information circulating in the bloodstream. Areas free of the blood-brain barrier, where metabolites and hormones in the bloodstream can directly reach receptors on neurons, are circumventricular organs.

Injection of the neuronal tracer cholera toxin B into the ventromedial ARC vmARC resulted in the visualization of an elaborate network of projections to many targets within and outside the hypothalamus The vmARC is considered the site where information from the circulation can reach the hypothalamus, either via its connection with the circumventricular median eminence or through hormones that cross the blood-brain barrier and bind to its membrane-bound receptors.

The dense reciprocal interaction between the vmARC and the SCN provides the anatomical basis for the link between circulating metabolic information and the SCN This anatomical connection between vmARC and SCN may form the basis upon which the SCN is informed about circulating hormones and the vmARC about the time of the day Fig.

Gut-derived polypeptides have been shown to affect circadian rhythms. For example, gastrin-releasing peptide, a mediator of both feeding and locomotor activity, mediates light-like resetting of the SCN 82 ; peptide tyrosine-tyrosine has also been shown to correlate with alterations to wakefulness and sleep architecture However, the effect of peptide tyrosine-tyrosine and gastrin-releasing peptide is presumably mediated via vagal afferents that travel through the autonomic nervous system to the SCN rather than directly from the vmARC.

Several brain regions have been associated with energy homeostasis. These regions are the VMH, PVN, DMH, and ARC located at the mediobasal hypothalamus.

Destruction of VMH, PVN, and DMH results in obesity, whereas ablation of the lateral hypothalamus results in anorexia At the molecular level, the melanocortin system plays a major role in the neural control of energy homeostasis 85 , Leptin, a satiety signal, stimulates proopiomelanocortin POMC - and cocaine- and amphetamine-regulated transcript-expressing neurons within the ARC to produce α-melanocyte-stimulating hormone α-MSH , which subsequently activates the melanocortin 4 receptor MC4R and results in decreased food intake and increased energy expenditure 87 , In humans, mutations in the POMC and MC4R genes are associated with morbid obesity 89 — In parallel, leptin suppresses a distinct set of neuropeptide Y NPY - and agouti-related protein AgRP -expressing neurons within the ARC.

Thus, agonists α-melanocyte-stimulating hormone and antagonists AgRP of the MC4R determine the weight-regulating effects of leptin in the central nervous system.

Leptin can be the bridge between energy homeostasis and circadian control, due to its circadian oscillation see Section IV.

D and expression of its receptor in several hypothalamic regions. Activation of vmARC neurons by systemic administration of the ghrelin mimetic GH-releasing peptide-6 combined with SCN tracing showed that vmARC neurons transmit feeding-related signals to the SCN This injection induced Fos in the vmARC and resulted in attenuation of light-induced phase delay in mice and light-induced Fos expression in the SCN in rats Administration of ghrelin to SCN slices or SCN explants in vitro caused phase shifts in Perluc reporter gene expression.

However, administration of ghrelin to wild-type mice only caused phase shifts after 30 h of food deprivation, whereas ip injection of ghrelin did not cause phase shifts in wild-type mice fed ad libitum Thus, it seems that ghrelin and leptin may affect the SCN directly or through their effect on the ARC, which is then relayed to the SCN Fig.

Hypothalamic neuropeptides, such as NPY, AgRP, and POMC, are also expressed according to a pronounced diurnal rhythm, although the extent to which these oscillations are entrained by feeding, light, or nutrient signaling remains uncertain In addition to its being a clock-controlled output gene, NPY is involved in communicating nonphotic signals to the SCN via the intergeniculate leaflet Fig.

In addition, serotonergic signaling pathways from the raphe nuclei that influence feeding and energy metabolism in the hypothalamus have been shown to modulate both SCN oscillations and sleep Fig.

Therefore, these signaling systems appear to be involved in a feedback loop that links feeding and metabolic state to the SCN. ARC neurons project to multiple nuclei involved in feeding behavior 99 , — , such as the lateral hypothalamus, which produces the hunger-stimulating neuropeptides melanin-concentrating hormone MCH , orexin A, and orexin B — Fig.

Targeted deletion studies of MCH resulted in hypophagic lean mice with a high metabolic rate and demonstrated that MCH acts downstream of leptin and the melanocortin system Orexins A and B are two neuropeptides generated from a single transcript that display a circadian rhythm of expression and are strongly induced by fasting , Indeed, mutant mice, in which Clock function is impaired, exhibit significantly higher energy intake and almost complete ablation of rhythmic expression in Cart and Orexin Intracerebroventricular injection of orexin A stimulates food intake acutely in rats, in part through excitation of NPY in the ARC , Orexins also play a role in the regulation of sleep-wake rhythms because mutations in the orexin B receptor , and deletion of the orexin gene caused narcolepsy and obesity , All these findings demonstrate the intricate relationships between circadian rhythms and energy homeostasis.

Many hormones involved in metabolism, such as insulin , glucagon , adiponectin , corticosterone , leptin, and ghrelin , , have been shown to exhibit circadian oscillation. Leptin, an adipocyte-derived circulating hormone that acts at specific receptors in the hypothalamus to suppress appetite and increase metabolism, is extremely important in obesity.

Leptin exhibits striking circadian patterns in both gene expression and protein secretion, with peaks during the sleep phase in humans Neither feeding time nor adrenalectomy affected the rhythmicity of leptin release. However, ablation of the SCN has been shown to eliminate leptin circadian rhythmicity in rodents, suggesting that the central circadian clock regulates leptin expression In addition, SCN-lesioned rats, as opposed to intact animals, showed no elevation in plasma free fatty acids FFAs after ip administration of leptin, suggesting a role for SCN in leptin function In addition to the endocrine control, the circadian clock has been reported to regulate metabolism and energy homeostasis in peripheral tissues , Some examples are glycogen phosphorylase , cytochrome oxidase , lactate dehydrogenase , acetyl-CoA carboxylase , , malic enzyme, fatty acid synthase, glucosephosphate dehydrogenase , and many more.

Moreover, lesion of rat SCN abolishes diurnal variations in whole body glucose homeostasis , altering not only rhythms in glucose utilization rates but also endogenous hepatic glucose production. Indeed, the SCN projects to the preautonomic PVN neurons to control hepatic glucose production Similarly, glucose uptake and the concentration of the primary cellular metabolic currency ATP in the brain and peripheral tissues have been found to fluctuate around the circadian cycle , , In addition, a large number of nuclear receptors involved in lipid and glucose metabolism has been found to exhibit circadian expression The effect of metabolism on the master or peripheral clocks could arise from feeding, food metabolites, or hormones whose secretion is controlled by food or its absence.

Several studies have identified single nutrients capable of resetting or phase-shifting circadian rhythms, such as glucose — , amino acids , sodium , , ethanol , , caffeine , thiamine , , and retinoic acid , In addition to nutrients, hormones that regulate metabolism can also induce or reset circadian rhythms through regulation of clock gene expression.

For example, in Rat-1 fibroblast cultures, insulin causes an acute induction of Per1 mRNA production Glucocorticoids were shown to induce circadian gene expression in cultured rat-1 fibroblasts and transiently change the phase of circadian gene expression in liver, kidney, and heart , Interestingly, it was recently reported that leptin causes up-regulation of Per2 and Clock gene expression in mouse osteoblasts that exhibit endogenous circadian rhythms Recent experiments have suggested that cellular energy levels are capable of influencing rhythms CLOCK and its homolog NPAS2 can bind efficiently to BMAL1 and consequently to E-box sequences in the presence of reduced nicotinamide adenine dinucleotides NADH and NADPH Fig.

However, the role of redox on circadian rhythms needs to be investigated in vivo. A, High NAD P H levels promote CLOCK:BMAL1 binding to E-box sequences leading to the acetylation of BMAL1 and expression of Per s, Cry s, and other clock-controlled genes.

The negative feedback loop, PERs:CRYs binds to CLOCK:BMAL1, and consequently PERs are acetylated. B, Expression of Bmal1 and Rev-erb α genes are controlled by PPARα and binding of RORs to RORE sequences. RORs need a coactivator, PGC-1α, which is phosphorylated by AMPK.

SIRT1 activation leads to PGC-1α deacetylation and activation. Ac-ADP-r, Acetyl adenosine diphosphate ribose; NAM, nicotinamide. Interestingly, AMP-activated protein kinase AMPK , an important nutrient sensor, has been found to phosphorylate Ser of CKIε, resulting in increased CKIε activity and degradation of mPER2.

mPER2 degradation leads to a phase advance in the circadian expression pattern of clock genes in wild-type mice In addition, the expression profile of clock-related genes, such as Per1 and Cry2 , in skeletal muscle in response to 5-aminoimidazole-carboxamide riboside, an AMPK activator, as well as the diurnal shift in energy utilization, is impaired in AMPKγ 3 subunit knockout mice Because AMPK has been implicated in feeding regulation and it serves as an energy sensor, it could be one of the links to integrate the circadian clock with metabolism Fig.

Another protein, recently found to link metabolism with the circadian clock, is SIRT1. Recent studies show that SIRT1 interacts directly with CLOCK and deacetylates BMAL1 and PER2 , Fig. When acetylated, PER2 and possibly BMAL1 are more stable Fig. SIRT1 then becomes activated and starts deacetylating BMAL1, PER2, and histones Deacetylated PER2 is further phosphorylated and degraded, and a new cycle begins.

SIRT1 is recruited to the Nampt promoter and contributes to the circadian synthesis of its own coenzyme Similarly to the control of the circadian clock on metabolism, feeding is a very potent synchronizer zeitgeber for peripheral clocks Fig.

Limiting the time and duration of food availability with no calorie reduction is termed restricted feeding RF 39 , , , Animals that receive food ad libitum everyday at the same time for only a few hours adjust to the feeding period within a few days and consume their daily food intake during that limited time 38 , , Restricting food to a particular time of day has profound effects on the behavior and physiology of animals.

Two to 4 h before the meal, the animals display food anticipatory behavior, which is demonstrated by an increase in locomotor activity, body temperature, corticosterone secretion, gastrointestinal motility, and activity of digestive enzymes , , , , all of which are known output systems of the biological clock.

RF is dominant over the SCN and drives rhythms in arrhythmic and clock mutant mice and animals with lesioned SCN, regardless of the lighting conditions , — In most incidents, RF affects circadian oscillators in peripheral tissues, such as liver, kidney, heart, and pancreas, with no effect on the central pacemaker in the SCN 39 , , , , , , Thus, RF uncouples the SCN from the periphery, suggesting that nutritional regulation of clock oscillators in peripheral tissues may play a direct role in coordinating metabolic oscillations Many physiological activities that are normally dictated by the SCN master clock, such as hepatic P activity, body temperature, locomotor activity, and heart rate, are phase-shifted by RF to the time of food availability , , , , As soon as food availability returns to normal, the SCN clock, whose phase remains unaffected, resets the peripheral oscillators The location of this food-entrainable oscillator has been elusive.

Lesions in the dorsomedial hypothalamic nucleus DMH — , the brainstem parabrachial nuclei , , and the core and shell regions of nucleus accumbens , revealed that these brain regions may be involved in food-entrainable oscillator output, but they cannot fully account for the oscillation Neither vagal signals nor leptin are critical for the entrainment , CLOCK or BMAL1 and other clock genes have been shown not to be necessary for food anticipatory activity.

However, it has recently been demonstrated that mPer2 mutant mice did not exhibit wheel-running food anticipation , Thus, the effect of RF on circadian rhythms warrants further study.

Calorie restriction CR refers to a dietary regimen low in calories without malnutrition. In addition to the increase in life span, CR also delays the occurrence of age-associated pathophysiological changes, such as cancer, diabetes, kidney disease, and cataracts — Theories on how CR modulates aging and longevity abound, but the exact mechanism is still unknown As opposed to RF, CR entrains the clock in the SCN — , indicating that calorie reduction could affect the central oscillator.

CR during the daytime affects the temporal organization of the SCN clockwork and circadian outputs in mice under light-dark cycle. In addition, CR affects photic responses of the circadian system, indicating that energy metabolism modulates gating of photic inputs in mammals These findings suggest that synchronization of peripheral oscillators during CR could be achieved directly due to the temporal eating, as has been reported for RF , , , or by synchronizing the SCN — , which in turn sends humoral or neuronal signals to entrain the peripheral tissues 38 , During intermittent fasting IF , food is available ad libitum every other day.

IF-treated mice eat on the days they have access to food approximately twice as much as those having continuous access to food , Similarly to calorically restricted animals , IF-fed animals exhibit increased life span in comparison with the ad libitum -fed control as well as improved glucose metabolism, cardio-protection, neuro-protection , — , and increased resistance to cancer The IF-induced beneficial effects are thought to occur independently of the overall caloric intake, but the underlying mechanisms are still unknown.

One suggested mechanism is stimulation of cellular stress pathways induced by the IF regimen , , Recently, it has been shown that when food was introduced during the light period, mice exhibited almost arrhythmicity in clock gene expression in the liver.

Unlike daytime feeding, nighttime feeding yielded rhythms similar to those generated during ad libitum feeding The fact that IF can affect circadian rhythms differently depending on the timing of food availability suggests that this regimen affects the SCN clock, similarly to CR.

SCN resetting by IF and CR could be involved in the health benefits conferred by these regimens The daily rhythm in adipose leptin production strongly suggests a direct control of adipose tissue activity by the biological clock Indeed, injection of the pseudorabies virus into white adipose tissue WAT led to labeling in SCN neurons , WAT is innervated by the sympathetic nervous system leading to the mobilization of lipid stores , and by the parasympathetic nervous system resulting in anabolism To test whether the SCN uses its projections to preautonomic PVN neurons to control the mobilization of lipid stores, similarly to its control over hepatic glucose production see Section IV.

A , the γ-aminobutyric acid-antagonist bicucilline was infused into the PVN, and plasma glucose, leptin, and FFA levels were measured Contrary to plasma glucose concentrations, plasma FFA and plasma leptin concentrations were not affected by bicucilline treatment in the PVN.

Also, PVN lesions did not attenuate fasting-induced lipid mobilization Viral tracing from WAT, besides the PVN, was found especially in the MPOA, an area implicated in lipid metabolism, the DMH, and the ARC , Thus, it seems that the SCN uses different outputs to control glucose via the PVN and lipid via the MPOA metabolism Circadian clocks have been shown to be present in inguinal WAT, epididymal WAT, and brown adipose tissue 67 , , Diurnal variations in the sensitivity of adipose tissue to adrenaline-induced lipolysis persist ex vivo , suggesting that the intrinsic nature of the adipocyte exhibits a diurnal variation Recent transcriptome studies revealed rhythmic expression of clock and adipokine genes, such as resistin, adiponectin, and visfatin, in visceral fat tissue The expression of these mediators is blunted in obese patients , , Fatty acid transport protein 1 Fatp1 , fatty acyl-CoA synthetase 1 Acs1 , and adipocyte differentiation-related protein Adrp exhibit diurnal variations in expression, suggesting that nocturnal expression of FATP1, ACS1, and ADRP will promote higher rates of fatty acid uptake and storage of triglyceride in rodents Recent molecular studies established the involvement of BMAL1 activity in the control of adipogenesis and lipid metabolism in mature adipocytes.

Furthermore, overexpression of BMAL1 in adipocytes increased lipid synthesis activity. These results indicate that BMAL1, a master regulator of circadian rhythm, also plays important roles in the regulation of adipose differentiation and lipogenesis in mature adipocytes Because these receptors sense various lipids, vitamins, and fat-soluble hormones, they serve as direct links between nutrient-sensing pathways and the circadian control of gene expression.

The circadian rhythmicity of a nuclear receptor family member, PPARα, provides an example of a reciprocal link between circadian and lipid metabolic processes.

The CLOCK:BMAL heterodimer mediates transcription of PPARα, which subsequently binds to the peroxisome-proliferator response element PPRE and activates transcription of Bmal1 — Figs. Bmal1 has also been shown to be regulated by PPARγ in cells of the aorta PPARα regulates the transcription of genes involved in lipid and glucose metabolism upon binding of endogenous FFAs.

Thus, PPARα may play a unique role at the intersection of circadian and lipid metabolic pathways. Another example for the relationship between nuclear receptors and the biological clock is seen with retinoic acid. Retinoic acid has been shown to up-regulate Per1 and Per2 expression in an E-box-dependent manner in mouse fibroblast NIH3T3 cells Similarly, retinoic acid can phase-shift Per2 expression in vivo and in serum-induced smooth muscle cells in vitro However, when retinoic acid is administered to cells expressing the retinoic acid receptors RARα or RXRα, the ligand-receptor complex competes with BMAL1 for binding to CLOCK or NPAS2 in vascular cells.

An important candidate to link between the circadian clock and lipid metabolism is REV-ERBα. This proadipogenic transcription factor, whose levels increase dramatically during adipocyte differentiation , exhibits striking diurnal variations in expression in murine adipose tissue and rat liver Ectopic REV-ERBα expression in 3T3L1 preadipocytes promotes their differentiation into mature adipocytes In addition to its role in lipid metabolism and adipocyte differentiation, REV-ERBα is a negative regulator of Bmal1 expression 58 , as mentioned above Figs.

In contrast, RORα, which regulates lipogenesis and lipid storage in skeletal muscle, is a positive regulator of Bmal1 expression 60 , , Figs. Interestingly, CLOCK:BMAL1 heterodimer regulates the expression of both Rev-erb α and Ror α 58 , 60 , Figs.

Mice deficient in RORα or REV-ERBα have impaired circadian rhythms of locomotor activity and clock gene expression 58 , The PPARγ coactivator, PGC-1α peroxisome proliferator-activated receptor-coactivator 1a , a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice.

PGC-1α stimulates the expression of Bmal1 and Rev-erb α through coactivation of the ROR family of orphan nuclear receptors , Fig. Mice lacking PGC-1α show abnormal diurnal rhythms of activity, body temperature, and metabolic rate due to aberrant expression of clock genes and those involved in energy metabolism.

Analyses of PGC-1α-deficient fibroblasts and mice with liver-specific knockdown of PGC-1α indicate that it is required for cell-autonomous clock function Acetylated PGC-1α is also a substrate for SIRT1 see Section IV. E Fig. Thus, PPARα, PPARγ, REV-ERBα, RORα, and PGC-1α are key components of the circadian oscillator that integrate the mammalian clock and lipid metabolism.

The interconnection between the clock core mechanism and lipogenic and adipogenic pathways emphasizes why clock disruption leads to metabolic disorders see Section V.

Few studies show that a high-fat diet leads to minimal effects on the rhythmic expression of clock genes in visceral adipose tissue and liver , However, recent studies have shown that introduction of a high-fat diet to animals leads to rapid changes in both the period of locomotor activity in constant darkness and to increased food intake during the normal rest period under light-dark conditions These changes in behavioral rhythmicity correlated with disrupted clock gene expression within hypothalamus, liver, and adipose tissue, as well as with altered cycling of hormones and nuclear hormone receptors involved in fuel utilization, such as leptin, TSH, and testosterone in mice, rats, and humans — Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity In addition to the disruption of clock gene expression, high-fat diet induced a phase delay in clock and clock-controlled genes Recently, AMPK has been found to phosphorylate Ser of CKIε, resulting in increased CKIε activity and degradation of mPER2.

mPER2 degradation leads to a phase advance in the circadian expression pattern of clock genes in wild-type mice see Section IV. As the levels of mAMPK decline under a high-fat diet , it is plausible that the changes seen in the expression phase of genes under a high-fat diet are mediated by changes in AMPK levels.

These results correlated with reduction in c-FOS and P-ERK expression in the SCN in response to light-induced phase shifts Fluctuations in body weight have been associated with changes in day length in various species, suggesting a central role for the circadian clock in regulating body weight.

For example, in Siberian hamsters, modulation of body weight depends on photoperiod acting via the temporal pattern of melatonin secretion from the pineal gland , In studies performed on sheep, adipose tissue leptin levels were modulated by day length independently of food intake, body fatness, and gonadal activity.

In addition, increasing the length of the photoperiod resulted in increased activity of the lipogenesis-promoting proteins lipoprotein lipase and malic enzyme, independent of the nutritional status , In humans, studies have demonstrated an increased incidence of obesity among shift workers — see Section V.

In obese subjects, leptin retains diurnal variation in release, but with lower amplitude Leptin h levels were lower in obese compared with nonobese adolescent girls, suggesting that blunted circadian variation may play a role in leptin resistance and obesity Circadian patterns of leptin concentration were distinctly different between adult women with upper-body or lower-body obesity, with a delay in peak values of leptin of approximately 3 h in women with upper-body obesity Indeed, leptin and the leptin receptor knockouts in animals or mutations in humans have been demonstrated to produce morbid, early onset obesity, hypoleptinemia, hyperphagia, hyperinsulinemia, and hyperglycemia — Similarly to leptin, the rhythmic expression of resistin and adiponectin was greatly blunted in obese KK and obese, diabetic KK-A y mice In humans, circulating adiponectin levels exhibit both ultradian pulsatility and a diurnal variation.

In the latter case, the pattern of adiponectin release is out of phase with leptin with a significant decline at night, reaching a nadir in the early morning In obese subjects, adiponectin levels were significantly lower than lean controls, although the obese group had significantly higher average pulse height and valley concentrations In rats, melatonin, a synchronizer of the SCN clock, decreased weight gain in response to high-fat diet and decreased plasma leptin levels within 3 wk.

These effects were independent of total food consumption Thus, it seems that the circadian clock plays a major role in determining body weight probably by influencing the expression and secretion of hormones see Section V. Recent studies have suggested that disruption of circadian rhythms in the SCN and peripheral tissues may lead to manifestations of the metabolic syndrome 5 , , Circadian control of glucose metabolism is implicated by the variation in glucose tolerance and insulin action across the day , Evidence suggests that loss of circadian rhythmicity of glucose metabolism may contribute to the development of metabolic disorders, such as type 2 diabetes, in both rodents — and humans , For example, daily cycles of insulin secretion and glucose tolerance are lost in patients with type 2 diabetes , , as are daily variations in plasma corticosterone levels and locomotor activity in streptozotocin-induced diabetic rats , In addition, some clock genes exhibited altered expression in the liver, heart, and kidney in diabetic animals 23 , , These findings indicate that a critical relationship exists between endogenous circadian rhythms and diabetes.

The findings also suggest that the time of day may be an important consideration for the diagnosis and treatment of metabolic disorders, such as type 2 diabetes , Interestingly, the oscillations of clock Bmal1 , Per1 , Per2 , Cry1 , Cry2 , and Dbp and adipokine genes were mildly suppressed in the adipose tissue of obese KK mice and greatly suppressed in the adipose of obese, diabetic KK-A y mice compared with wild-type mice Similarly, obese diabetic mice exhibited circadian oscillation of most genes in the liver, but some genes had attenuated, but still rhythmic, expression In addition, in type 1 diabetes patients, lipolysis increased earlier in the evening than in healthy controls and remained elevated throughout the night, indicating that lipolysis shows a distinct circadian rhythm that is altered in type 1 diabetes patients These findings point to the tight relationship between disruption of circadian rhythms and metabolic disorders.

The most compelling linkage between metabolic disorders and the circadian clock is demonstrated by the phenotypes of clock gene mutants and knockouts. Several strains with varying effects on metabolism have thus far been examined. Loss of circadian rhythms in Clock Δ 19 mutant mice was accompanied by attenuated expression of hypothalamic peptides associated with energy balance, such as ghrelin and orexin Insulin administration caused significantly greater hypoglycemia in Clock Δ 19 mutant mice than in wild-type mice In Clock Δ 19 on a Jcl:ICR background, serum levels of triglyceride and FFA were significantly lower than in wild-type control mice, whereas total cholesterol and glucose, insulin, and leptin levels did not differ However, in Jcl:ICR Clock Δ 19 mutant mice, high-fat diet amplified the diurnal variation in glucose tolerance and insulin sensitivity, and obesity was attenuated through impaired dietary fat absorption Triglyceride content in the liver was significantly less increased in Jcl:ICR Clock Δ 19 mutant mice fed a high-fat diet compared with wild-type mice.

Jcl:ICR Clock Δ 19 mutant mice had attenuated daily rhythms of Acsl4 acyl-coenzyme A synthetase long-chain 4 and Fabp1 fatty acid binding protein 1 gene expression in the liver under both normal and high-fat diet conditions compared with wild-type mice, which could have led to the attenuated accumulation of triglycerides in the liver under a high-fat diet Although the effects on metabolism were variable, due to strain differences, the overall picture is that disruption of the clock gene leads to disruption of metabolic pathways.

Liver-specific deletion of Bmal1 showed a direct effect of the liver clock on glucose metabolism, as exhibited by hypoglycemia during fasting, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes Thus, it seems that CLOCK and BMAL1 regulate the recovery from insulin-induced hypoglycemia, glucose tolerance, insulin sensitivity, and fat absorption.

The Per2 gene has also been implicated in cell cycle regulation and was suggested to function as a tumor suppressor in thymocytes 8. Because bone and adipose tissue share a common ontogeny, it is possible that these findings may also have implications for adipogenesis Alterations in lipid and glucose homeostasis also occur with mutations in clock-related genes, such as the Nocturnin , a deadenylase involved in posttranscriptional regulation of rhythmic gene expression , This phenotype is probably due to lack of rhythmicity in genes important for lipid uptake or metabolism because these mice exhibit loss of these lipid pathways Sleep is one of the clock-controlled output systems.

A large body of evidence accumulated thus far suggests that short sleep duration is associated with increased body mass index BMI; weight in kilograms divided by the square of height in meters and elevated incidence of type 2 diabetes — Clinical studies have also identified changes in many aspects of energy metabolism after just a few days of partial sleep restriction.

Furthermore, short sleepers have significantly reduced circulating levels of the anorectic hormone leptin, increased levels of the orexigenic hormone ghrelin, and increased hunger and appetite , These neuroendocrine changes could explain, in part, reports of increased appetite after sleep loss Indeed, previous studies have reported that obese patients were sleepier during the day and more likely to experience disturbed sleep at night compared with normal-weight controls Daytime sleepiness could not wholly be explained by disturbed nighttime sleep, suggesting that a circadian abnormality likely underlies the daytime sleepiness observed in the obese patients Morning levels of cytokines associated with obesity, e.

In addition, sleep deprivation leads to obesity and affects plasma leptin levels The diurnal amplitude of leptin was reduced during 88 h of sleep deprivation and returned toward normal during the period of recovery sleep Shift work is another example in which the normal synchrony between the light-dark cycle, sleeping, and eating is disturbed.

Shift work has been associated with cardiovascular disease, obesity, diabetes, and other metabolic disturbances , Even when a group of students were switched from daytime activity with the last meal between and h to nighttime activity with the last meal at to h, after 3 wk they exhibited much higher insulin and glucose levels throughout the 24 h than the daytime students Among obese adults with type 2 diabetes, night-eating disorder was reported more frequently People who habitually sleep less than 6 h or more than 9 h per night have increased risk of developing type 2 diabetes and impaired glucose tolerance It has been reported that obesity, high triglycerides, and low concentrations of high-density lipoprotein cholesterol seem to cluster together more often in shift workers than in day workers , Similarly, duration of shift work was directly related to BMI and waist to hip ratio independent of age, sex, smoking status, physical activity, and educational level , , Recently, it has been reported that subjects who experienced 38 h of continued wakefulness still exhibit significant endogenous circadian rhythms in leptin, glucose, and insulin with peaks around the usual time of waking Feeding during the period of wakefulness was associated with systematic increases in leptin levels, whereas fasting during recovery sleep was associated with systematic decreases in leptin levels, glucose, and insulin Shea et al.

These findings point to the adipocyte as an important factor in the development of obesity associated with shift work. Thus, shift work and sleep deprivation are associated with increased adiposity, findings that have been linked to the sleep-associated peak in leptin secretion.

High-fat diet and obesity also affect sleep itself. Mice fed a high-fat diet have increased sleep time, particularly in the non-rapid eye movement NREM stage, but decreased sleep consolidation On the other hand, acute administration of leptin decreases rapid eye movement sleep and increases NREM sleep time in rats It is beyond the scope of this review to explore the interconnection between metabolism and sleep.

The prominent influence of the circadian clock on human physiology is demonstrated by the temporal and pronounced activity of a plethora of systems, such as sleep-wake cycles, feeding behavior, metabolism, and physiological and endocrine activity.

Western lifestyle leads to high food consumption, inactivity during the active period, enhanced activity in the rest period, and shortened sleep period. This lifestyle may cause high parasympathetic output to the viscera leading to obesity, hyperinsulinemia, and hyperlipidemia, or high sympathetic output to the muscle and heart leading to vasoconstriction and hypertension.

Indeed, disrupted biological rhythms might lead to attenuated circadian feeding rhythms, disrupted metabolism, cancer proneness, and reduced life expectancy. Disruptions of rhythms together with genetic background increase the risk to develop these health complications.

Findings in murine models show the strong link between genetic background and circadian rhythm disruption in determining the severity of metabolic disorders. Unfortunately, circadian rhythms in metabolism are often overlooked in both treatments and design of clinical and animal studies.

Because food components and feeding time have the ability to reset bodily rhythms, it is of extreme importance to further investigate the relationship between food, feeding, and the biological clock at the molecular level.

Resetting the biological clock by food or feeding time may lead to better functionality of physiological systems, preventing metabolic disorders, promoting well-being, and extending life span. This work was supported by Nutricia Research Foundation Grant , E3 and Binational USA—Israel Science Foundation BSF Grant Wyatt SB , Winters KP , Dubbert PM Overweight and obesity: prevalence, consequences, and causes of a growing public health problem.

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Everything You Need To Know About The Circadian Rythm

Circadian rhythm metabolism -
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Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell ; : 84— Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA. Through contractile forces, skeletal muscle provides the essential means by which animals achieve movement, including the fundamental acts of survival such as seeking sustenance and shelter and avoiding predators and environmental hazards Figure 2 G.

Skeletal muscle burns different fuels depending on the metabolic demand, relying more exclusively on glucose during fed conditions and resistance training but switching primarily to lipid utilization during fasting and prolonged endurance exercise Although earlier estimates identified circadian genes in mouse skeletal muscle , more recent analyses have indicated that over genes exhibit a circadian rhythm in the tissue Genetic knockout models have been highly informative in uncovering the specific regulatory roles of the individual clock components in skeletal muscle metabolism.

Muscle-specific inducible deletion of BMAL1 revealed a striking deficiency in insulin-stimulated glucose uptake These studies suggested that the activating arm of the clock is critical in orchestrating the switch in fuel source from lipid to glucose that occurs during the sleep-to-wake transition.

Additionally, rescuing BMAL1 skeletal muscle expression in the context of a whole-animal knockout partially prevented decreases in overall activity and body weight and indicated that functional muscle rhythm has a profound impact on systemic energy homeostasis Further underscoring the importance of clock control in muscle physiology is the finding that the key muscle differentiation transcription factor, MyoD, is circadian, and disruption of its normal expression pattern due to either Clock Δ 19 mutation or Bmal1 deletion results in altered muscle structure and function The repressive arm of the clock also contributes to skeletal muscle circadian programming.

Rev-erbα controls skeletal muscle lipid utilization, at least in part, through the direct transcriptional regulation of lipoprotein lipase as evidenced by whole-animal Rev-erb α deletion Rev-erbα was also found to positively impact exercise capacity and oxidative metabolism by impinging on the LKB1-AMPK-SIRT1-PGC-1α axis Interestingly, the transcriptional coactivator, PGC-1α, has previously been shown to induce the expression of both Bmal1 and Rev-erb α in skeletal muscle through the ROR nuclear receptors , ideally illustrating how the cross talk between the clock and metabolic networks goes in both directions.

Similar to other tissues such as brown adipose, the circadian control of skeletal muscle metabolism, particularly energy substrate selection, was likely evolved as a means of conservation. Carbohydrate utilization is lowered during the resting period, in which the animal is fasting, and lipid becomes the predominant energy source to preserve blood glucose levels for appropriate brain function.

Before waking, the clock again signals an anticipatory transition that reinstates glucose as the chief fuel source readying the animal for physical activity eg, food searching. Interestingly, the skeletal muscle peripheral clock not only dictates a rhythm of functional capacity but is itself subject to influence and synchronization by physical activity This helps to explain how the sedentary lifestyle of modern man has dramatically impacted evolutionary-instated mechanisms of entrainment.

The influence of physical activity on the skeletal muscle clock also indicates that exercise at different times of day may be more or less beneficial and therefore has significant implications for human health.

Additionally, understanding the molecular mechanism of circadian skeletal muscle control may provide potent therapeutic avenues for metabolic disease. Determining the downstream machinery through which the skeletal muscle clock switches between fuel sources or modulates glucose uptake could provide potent, tissue-specific targets to release the evolutionary brakes to counteract diabetic hyperglycemia or elevate fat-oxidizing capacity.

The human intestine is home to an enormous and highly diverse population of microorganisms, known as the gut microbiota, that has coevolved with its host to profoundly influence organismal energy homeostasis — The unique composition of the bacterial milieu confers different properties to the host, including influence over which nutrients can be extracted from foodstuffs Figure 2 H.

Given the circadian nature of food intake, it is not surprising that this dynamic is subject to regulation by the clock. Indeed, the counterregulatory activities of clock components, RORα, and Rev-erbα contribute to circadian cross talk between the intestinal epithelial cells and the gut microbiota through the transcriptional regulation of toll-like receptors The core clock also impacts the oscillation of bacterial species comprising the microbiota.

Whole-body genetic disruption of the host clock through Per1 and - 2 deletion resulted in loss of bacterial rhythm Moreover, environmental disruption of mouse and human circadian rhythm by phase-shifting light:dark cycles and jet lag across time zones, respectively, significantly altered hour bacterial patterning Circadian rhythm of the gut microbiota is similarly influenced by dietary composition.

HFD negatively impacts the diurnal cycling of the gut microbiota; however, time-restricting HFD to a portion of the dark, active period partially rescues normal oscillation From a therapeutic perspective, the gut microbiome offers unique avenues for developing novel treatment strategies Proof-of-concept studies have shown that bacteria that were genetically engineered to produce a beneficial metabolite were capable of reducing adiposity, insulin resistance, and hepatic steatosis in obese mice Similar probiotic approaches could be used to correct, re-establish, or maintain appropriate rhythm in the gut flora population.

The gut microbiome and its circadian patterning likely coevolved with the host to maximize calorie extraction, given the relative scarcity of food availability for thousands of years.

Additional investigation of the microbiome composition at different times of day could reveal specific oscillating bacterial subtypes responsible for diurnal variation in the capacity for processing foodstuffs.

A central thesis of this review is that evolutionarily selected circadian clock mechanisms are impacted by modern lifestyles. This new challenge raises the possibility of circadian-based therapeutic strategies that modulate the activities of core clock components.

For example, Rev-erbα agonists have been suggested to increase energy expenditure and reduce adiposity in diet-induced obese mouse models , enhance exercise capacity , and suppress anxiety-like behavior Nevertheless, despite these potential beneficial effects, targeting core clock components carries a risk, given their functional presence in every cell of the body.

The diverse metabolic roles of clock factors in various tissues further complicate the systemic use of ubiquitous agonists or antagonists. To this end, delving deeper into the tissue-specific mechanisms through which the clock controls key metabolic pathways offers a selective advantage with lower risk for adverse side effects.

Importantly, taking the evolutionary purpose of various clock-controlled functions into account provides a valuable filter through which to pinpoint the networks that might be most clinically efficacious. For example, can we develop targeted therapeutic strategies to stop clock-mediated down-regulation of brown fat heat production, increase muscle glucose sensitivity throughout the day, or attenuate aberrant hepatic lipogenesis in individuals with sleep disruption?

Unbiased small-molecule and small interfering RNA screening could be used to identify key, tissue-specific surface receptors and intracellular factors that mediate circadian metabolic control in a similar manner as has been previously employed for more general oscillatory modulators — This strategy has the potential to yield highly potent and selective novel therapies without global detriment to the core clock.

Not only is this concept feasible, but the likelihood is that many commercially available drugs are already functioning in this very manner. This finding demonstrates the profound importance of determining the most appropriate temporal window of therapeutic opportunity for each for drug target.

Indeed, reevaluation of dosage and time of delivery for existing drugs that target circadian metabolic programs may improve efficacy or reduce negative side effects. Evolution has installed in us a powerful internal clock programmed to anticipate physiological events based on a battery of entrainment cues, including light, temperature, food, and physical activity.

To this end, uncovering the molecular underpinnings through which each tissue's circadian metabolism is coordinated, we may be able to tinker with the evolutionary toolbox and bring the clock up to modern times.

Research on circadian rhythm in the authors' laboratories was supported by National Institutes of Health Grant R01 DK to M. Dobzhansky T. Nothing in biology makes sense except in the light of evolution. Am Biol Teach.

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Both RORα and RORγ have been implicated in the control of energy homeostasis and regulation of lipid and glucose metabolism. Deficiency of Rora , but not Rorc , in mice fed an obesogenic high-fat diet HFD led to reduced levels of adiposity and hepatic triglyceride levels, inflammation, and insulin resistance in comparison with WT mice 87 — Multiple organs contributed to this phenotype.

In skeletal muscle, compared with WT mice, increased levels of AKT and phosphorylated AKT and enhanced glucose uptake were observed in Rora -deficient mice Upon Rora knockout, genes related to lipid synthesis were downregulated in the liver, and inflammatory genes were also downregulated in white adipocyte tissue 87 , However, a previous study reported that RORα-null mice had increased triglyceride accumulation and lipogenic gene expression in the liver 90 , leading researchers to revisit the function of RORs in liver.

In BAT, Ucp1 and other thermogenic genes were upregulated upon Rora knockout. Consistently, primary brown adipocytes from Rora -deficient mice displayed a higher metabolic rate Like RORα, RORγ plays important roles in the metabolic regulation of multiple organs.

Rorc -deficient mice show decreased adipocyte sizes and high insulin sensitivity with improved control of circulating free fatty acids compared with WT controls.

HFD-fed Rorc -deficient mice are also protected from hyperglycemia and insulin resistance Consistently, Rorc expression in the adipose stromal vascular fraction from obese human subjects is positively correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity In the liver, both whole-body Rorc -knockout and liver-specific Rorc -knockout mice display reduced levels of lipid in liver and blood, reduced cholesterol, and reduced bile acid pool size 93 , RORγ is highly expressed in skeletal muscle and controls the expression of genes that regulate muscle and fat mass, and modulates the production of reactive oxygen species An isoform of RORγ, called RORγt, is unique to inflammatory Th17 lymphocytes 96 , although its metabolic function has not been characterized.

Pers and Crys. Period , the first clock gene to be identified, has three homolog genes Per1 , Per2 , and Per3 in mammals 97 — Cryptochrome Cry has two homologs, Cry1 and Cry2 Although PERs and CRYs lack a DNA-binding domain and therefore are very unlikely to directly bind to DNA, they form a heterodimer that moves into the nucleus upon phosphorylation by casein kinase 1 CK1 , and inhibit the transcriptional activity of BMAL1-CLOCK heterodimer — Per1- or Per2- deficient mice, but not Per3 -deficient mice, display disrupted locomotor activity rhythms in extended exposure to constant darkness.

PERs have different functions in the regulation of metabolism Per1 -deficient mice display elevated blood pressure involving a mechanism of renal sodium reabsorption Rhythms of glucocorticoid secretion and diurnal feeding rhythms are disrupted in normal chow— and HFD-fed Per2 -deficient mice, resulting in decreased body weight gain in mice Per2 deficiency in ischemic hearts impairs carbohydrate utilization for oxygen-efficient glycolysis Mice lacking Cry1 or Cry2 alone display a phase-accelerated or a phase-delayed free-running period of locomotor activities, respectively, but the circadian rhythms are still robust.

Mice deficient in Cry1 , but not mice deficient in Cry2 , are resistant to HFD-induced obesity CRY regulates glucose homeostasis through several mechanisms. CRY represses gluconeogenesis by inhibiting protein kinase A—mediated phosphorylation of cAMP response element—binding protein CREB during fasting via blocking of glucagon-mediated increases in intracellular cAMP concentration CRY1 and CRY2 interact with glucocorticoid receptor GR in a ligand-dependent manner.

Core clock component—specific regulation of metabolic cycles. In addition to the common regulation of the core circadian clock interlocking feedback loop, groups of rhythmic genes are specifically regulated by certain core clock components.

Consistently, knockouts of these components share some common phenotypes, including disrupted locomotor activities in constant dark and tumorigenesis in mice with chronic jet lag , but each knockout model also has component-specific metabolic outcomes as discussed above.

To explore the underlying mechanisms of component-specific regulation, the genome occupancy of core clock components was determined, revealing that only a small proportion of binding sites are shared among all of the core components 25 , Further genome-wide rhythmic enhancer mapping using global run-on sequencing GRO-Seq identified that each phase of enhancers and downstream gene transcription is regulated by distinct core clock transcription factors TFs As summarized in Figure 2 , the BMAL1-CLOCK complex can bind to E-box motif , , while REV-ERBs, competing with RORs, bind on RORE motifs to regulate the expression of target genes whose enhancers or promoters contain these motifs 58 , 59 , In addition to the interaction with BMAL1-CLOCK, CRY1 broadly interacts with multiple nuclear receptors and modulates specific gene expression In addition to competing with ROR on ROREs, REV-ERBs can be tethered by cell type—specific TFs and regulate the rhythmic expression of another specific group of genes involved in metabolism The studies described above provide mechanisms of how core clock components bind in diverse ways on chromatin and directly regulate the oscillating expression of their target genes.

Core clock components can also indirectly regulate their target genes via downstream TFs. For example, BMAL1 activates the oscillating expression of Hlf , Tef , and Dbp which encode TFs in the PAR bZIP family to indirectly regulate the expression of rhythmic genes whose regulatory elements contain D-box , , REV-ERBs repress another D-box—binding transcription repressor, E4bp4 , which subsequently regulates the rhythmic expression of E4BP4 target genes These downstream TFs of each core clock component either independently or collaboratively regulate the rhythmic expression of circadian output genes.

Mechanisms of core clock component—specific regulation of target genes. Core clock components independently, or forming protein complexes, bind to specific chromatin regions to directly regulate circadian gene expression left. Each core clock component indirectly mediates circadian gene expression via downstream TFs right.

GR, glucocorticoid receptor; NRs, nuclear receptors. Figure 3 and Table 2 summarize the effects of these zeitgebers on biological rhythms and metabolic function.

Interactions between circadian rhythms and human physiology. Effects of environmental cues on biological rhythms and metabolism in humans. Follow the light. Night-shift workers display dyslipidemia, increased postprandial serum glucose and insulin , and increased circulating levels of several biomarkers of metabolic syndrome and inflammation Moreover, night-shift workers and people with long working hours have a high risk of obesity and diabetes — Experimental animal models have been used to demonstrate that circadian misalignment causes metabolic disturbances.

Here, we will discuss the effect of constant bright light LL , alternating dim and bright light dLL , and wavelengths of light on metabolism, including obesity, insulin resistance, and hepatic steatosis , Mice exposed to LL become behaviorally arrhythmic, and their SCNs become desynchronized The disruption of the peripheral clock was also observed in LL-exposed mice.

Mice exposed to LL developed obesity and hepatic steatosis, which was paralleled by an altered miRNA profile targeting the core clock gene Rev-erbα When an obesogenic diet is superimposed on LL, mice display a reduced amplitude of rhythms in the SCN and a complete abolishment of circadian rhythms of feeding pattern, energy expenditure, and insulin sensitivity During early development, the circadian system experiences a critical adjustment and is vulnerable to altered lighting conditions.

During lactation, short-term LL in pups caused a loss of rhythmicity, a reduction in vasoactive intestinal polypeptide—positive VIP-positive and arginine vasopressin—positive AVP-positive cells in the SCN, a reduction of PER1 expression in the SCN, reduced body weight gain, and loss of daily rhythms in plasma glucose and triglycerides These rhythmic metabolic disorders could not be restored in conditions of alternating light and dark LD after lactation In adult rats, LL downregulated plasma melatonin which is absent in most mouse models; refs.

Like LL, dLL exposes mice to light over the course of the hour day, but also provides a temporal cue for a hour day via different light intensity between day and night. Compared with LL, dLL has lesser impacts on circadian rhythms. Interestingly, compared with LD controls, both LL- and dLL-exposed mice display increased body mass and reduced glucose tolerance, but caloric intake and total daily activity output are not affected In the dLL-exposed mice, rhythms of Per1 and Per2 in the hypothalamus were attenuated, similarly to those of REV-ERB genes in the liver and adipose tissue In addition to LL, acute exposure to light in the night or a different wavelength also affects biological rhythms and metabolism.

Very short exposures to nocturnal light inhibit melatonin release, alter clock gene expression, and increase c-Fos expression in the SCN, and this effect is wavelength dependent: blue light has the greatest effect, whereas red light has no effect — Therefore, light as a predominant zeitgeber entraining the clock in the SCN is a major contributor to maintenance of organismal metabolic homeostasis.

You are what you eat. Diet composition is another important factor that affects the circadian clock. HFD disrupts circadian rhythms of locomotor and feeding activity in mice, with greater rhythmic expression of clock genes in fat than in liver Rhythmic transcriptome profiling identified a genome-wide reprogramming of the clock in the liver Using GRO-Seq to map HFD-specific circadian enhancers and quantify HFD-specific transcription rates, the DNA binding motifs for peroxisome proliferator—activated receptor PPAR and SREBP were shown to be enriched.

Further functional studies revealed an unexpected synchronization of two opposing lipid processes, lipid synthesis and oxidation, at a similar time of the day. The synchronization could be a maladaptive response to the overnutrition environment Ketogenic diets KDs are high-fat, adequate-protein, very-low-carbohydrate diets that induce fatty acid oxidation as an energy source and lead to the synthesis of ketone bodies.

This diet is used to treat epilepsy in children , to induce weight loss — , and to decrease the risk of heart disease , In mice, KD induced a profound circadian remodeling in the liver and gut in a tissue-specific manner.

KD drastically alters BMAL1 target genes in the liver, but not the gut, while highly diurnal rhythms of PPARα are only observed in the gut A low-calorie diet, which is known to boost fat metabolism and lifespan, enhances the magnitude of cyclic expression of circadian clock genes in Drosophila These results highlight the intricate reciprocal relationship between metabolism and food content—regulated peripheral clocks.

Eat on time. Meal time is known to be a dominant zeitgeber for peripheral tissue clocks such as the clock in the liver 81 , Eating during the active phase has healthy consequences for metabolism, while mistimed eating leads to metabolic disorders ,

The molecular circadian Wholesome mineral supplements regulates metabolic processes within the Circsdian, and the Circadian rhythm metabolism of these clocks Circadian rhythm metabolism tissues is essential for the maintenance of metabolic homeostasis. The Circadian rhythm metabolism of misalignment arises rhytum the megabolism responsiveness of tissues to the environmental cues that synchronize the clock zeitgebers. Metabolisk light is CCircadian dominant environmental cue Pancreatic function replacement technology the master clock of the suprachiasmatic nucleus, many other tissues are sensitive to feeding and fasting. When rhythms of feeding behavior are altered, for example by shift work or the constant availability of highly palatable foods, strong feedback is sent to the peripheral molecular clocks. Varying degrees of phase shift can cause the systemic misalignment of metabolic processes. Moreover, when there is a misalignment between the endogenous rhythms in physiology and environmental inputs, such as feeding during the inactive phase, the body's ability to maintain homeostasis is impaired. The loss of phase coordination between the organism and environment, as well as internal misalignment between tissues, can produce cardiometabolic disease as a consequence.

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