Back to Archived Journals » ChronoPhysiology and Therapy » Volume 6

Consequences of circadian dysregulation on metabolism

Authors Cisse YM, Nelson R

Received 7 June 2016

Accepted for publication 8 July 2016

Published 8 September 2016 Volume 2016:6 Pages 55—63

DOI https://doi.org/10.2147/CPT.S100363

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Marc Hébert



Yasmine M Cissé, Randy J Nelson

Department of Neuroscience, Neuroscience Research Institute, Behavioral Neuroendocrinology Group, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Abstract: Most organisms display endogenously produced rhythms in physiology and behavior of ~24 hours in duration. These rhythms, termed circadian rhythms, are entrained to precisely 24 hours by the daily extrinsic light–dark cycle. Circadian rhythms are driven by a transcriptional–translational feedback loop that is hierarchically expressed throughout the brain and body; the suprachiasmatic nucleus of the hypothalamus is the master circadian oscillator at the top of the hierarchy. Precise timing of the circadian clocks is critical for many homeostatic processes, including energy regulation and metabolism. Many genes involved in metabolism display rhythmic oscillations. Because circadian rhythms are most potently synchronized with the external environment by light, exposure to light at night potentially disrupts circadian regulation. Other potential disruptors of circadian organization include night shift work, social jet lag, restricted sleep, and misaligned feeding. Each of these environmental conditions has been associated with metabolic changes and obesity. The goal of this review is to highlight how disruption of circadian organization, primarily due to night shift work and exposure to light at night, has downstream effects on metabolic function.

Keywords: circadian disruption, light at night, obesity, shift work

Introduction

The prevalence of obesity and metabolic diseases has been increasing since the late 20th century, despite major efforts in raising public health awareness. More than two-thirds of Americans are considered overweight and obese (body mass index [BMI] >25 and >30, respectively).1 Estimates of global obesity prevalence are about half this rate, but are no less susceptible to these dramatic increases, nearly doubling since 1980.2,3 In addition to overall increased mortality, obesity is associated with the development of diabetes, cardiovascular diseases, certain cancers, reproductive dysfunction, as well as depression; all of these adverse health outcomes contribute to the increasing health care costs.416

Although obesity is considered to be the result of an energy imbalance, genetics and environmental factors play a role in affecting the magnitude of obesity in individuals.1719 The increased availability of food, especially calorie-dense foods, and shift toward a more sedentary lifestyle are considered primary contributors to obesity, but do not account for all the environmental changes that have occurred during the past 40 years. The rise of industrialization in the 20th century has increased human productivity, with the advent of electrical lighting to extend the workday, allow night shift work, as well as other social activities, to occur during the night. However, this technological intervention was accepted prior to a modern understanding of the circadian system and the detrimental effects of circadian disruption on physiology, behavior, and health.

Circadian rhythms are approximately, but not exactly, endogenous 24-hour rhythms in behavior and physiology that are synchronized to precisely 24 hours by the environmental day–night cycle. A functional and synchronized, or entrained, circadian system maintains homeostasis and temporally compartmentalizes energetically incompatible processes in order to maximize physiological efficiency. The circadian clock is deeply involved in maintaining metabolic, endocrine, and immunological homeostasis. It is therefore not unexpected that disrupting synchronizing signals would have severe consequences on metabolic functions. Many facets of an urban lifestyle exist in opposition to circadian synchrony: shift work, physical jet lag, social jet lag, exposure to light at night, sleep restriction, and misaligned feeding. Each of these environmental conditions have been associated with metabolic alterations.

This review highlights the associations between circadian disrupting lifestyle changes that have come about over the past century and their impact on metabolic functions. First, it provides a brief introduction to the circadian system. Then, it explores the influence of the circadian system on metabolism and reciprocal feedback from metabolic cues. Next, it presents insights gathered from experimental models of circadian disruption, namely forced desynchrony, light at night, and misaligned feeding and compares these findings with clinical and epidemiological data. Finally, the directions for future research are proposed.

Circadian rhythms

Circadian rhythms are a highly conserved system that maintains homeostasis by anticipating daily environmental changes. The suprachiasmatic nuclei (SCN) are a paired structure located in the anterior hypothalamus, which is considered the “master clock,” responsible for setting the phase of clocks located throughout the body. Timekeeping in the SCN is maintained by an autoregulatory transcriptional–translational feedback loop with a period of ~24 hours. The precise 24-hour period is imposed by the environmental light–dark cycle. Light is the most potent synchronizing cue, or zeitgeber, to the SCN. Light stimulates the intrinsically photosensitive retinal ganglion cells of the retina, which signal along the retinohypothalamic tract to the SCN.20 These signals cause rapid molecular changes in the cells of the SCN, altering the phase of the transcriptional–translational feedback loop and aligning it to the external time of day.21,22

The loop is initiated by proteins, namely circadian locomotor output cycles kaput (CLOCK) and brain muscle Arnt-like protein 1 (BMAL1). CLOCK and BMAL1 heterodimerize and drive expression of Period (Per) and Cryptochrome (Cry) genes through E-box enhancers. PER and CRY proteins form a secondary heterodimer that translocates back to the nucleus to inhibit their own transcription. This inhibitory arm of the loop is released by casein kinases, which tag PER for ubiquitin-mediated degradation. In addition to E-box motifs in the Per and Cry promoter regions, CLOCK and BMAL1 bind to E-boxes in promoter regions of various other genes (reviewed in Ko and Takahashi23).

One such target of CLOCK and BMAL1 are the nuclear receptors RAR-related orphan receptor alpha (RORα) and reverse-ErbA alpha (REV-ERBα), which enhance and repress Bmal1, respectively. This process acts as an auxiliary loop to fine-tune the primary loop. In addition to functions within the clock, CLOCK and BMAL1 regulate the expression of clock-controlled genes.23 Between direct targets and downstream effects of cycling clock genes, these molecular cycles regulate gene expression in various different systems, including, but not limited to, metabolism.

Circadian rhythms and metabolism

The SCN comprises the so-called master clock, but all cells in the body exhibit circadian rhythms. In mammals, it is the sole endogenous clock possessing the ability to be reset directly by light; therefore, peripheral clocks must rely on neural or humoral signaling from the SCN in order to maintain proper alignment with the time of day.24,25 It directly innervates local targets within the brain, such as the paraventricular nucleus, which through a polysynaptic pathway regulates rhythmic expression of melatonin.20,26 Similarly, SCN-derived vasopressin expressing neurons synapse upon the dorsomedial hypothalamus to regulate the daily rhythm in corticosterone by upstream regulation of the hypothalamus–pituitary–adrenal axis.27,28 These hormones act as humoral signals of circadian time to peripheral tissues.29 SCN connections in the paraventricular nucleus also regulate circadian rhythms in autonomic tone. Pre-autonomic fibers in the paraventricular nucleus synapse onto metabolic, immune, and endocrine tissues driving circadian rhythms in various physiological systems.3037

In addition to these SCN-derived signals, peripheral tissues also incorporate signals relevant to their homeostatic function, such as feeding state and metabolite ­abundance.3841 The liver plays an important role in maintaining metabolic homeostasis and is under heavy circadian control. Approximately 10% of the liver transcriptome and 20% of the proteome are circadian rhythmic; this stands on the higher end of the estimated circadian regulation of the mammalian transcriptome.4247 Most notably, hepatic glucose and triglyceride homeostasis, processes linked to functional expression of clock genes, are regulated in a circadian manner.4850

Animal models of circadian gene knockouts have played a crucial role in establishing the importance of clock genes in maintaining metabolic homeostasis. Knockouts of Clock and/or Bmal1 exhibit poor glucose tolerance and insulin sensitivity, as well as increased circulating triglycerides and cholesterol, and hepatic steatosis.5154 Loss of the inhibitory arm of the feedback loop similarly impairs glucose and lipid metabolism. Per-deficient mice exhibit altered lipid metabolism, decreasing body mass, and circulating lipids.55 Mutations in Cry genes impair gluconeogenesis.56 Elimination of REV-ERBs impairs lipid homeostasis,57 whereas addition of synthetic REV-ERBs to diet-induced obese mice resolves hyperlipidemia and hyperglycemia.58

As a peripheral clock, liver also incorporates external signals to determine local time. Food can entrain peripheral circadian clocks and food restriction can alter the phase of several circadian rhythms including glucocorticoid secretion.5962 Glucocorticoids can regulate 60% of the circadian transcripts in the liver in the absence of a functional SCN.63 Although traditionally considered stress hormones, glucocorticoids are primarily mediators of metabolism, generally favoring energy storage and fat deposition.64 High-fat diet consumption, in addition to weight gain, disrupts locomotor and molecular circadian rhythms in the adipose tissue and the liver.65 Specifically, the function of the liver clock is altered by inducing the production of additional metabolites in a PPARγ-dependent manner and impairing CLOCK:BMAL1 chromatin recruitment.66 The CLOCK:BMAL1 complex interacts with chromatin in a circadian manner through Sirtuin 6 (SIRT6), which polarizes transcription toward factors involved in lipid and carbohydrate metabolism.67 Sirtuins are NAD+-dependent deacetylases that act as integrators of cellular metabolism into circadian clock function.68,69 Specifically, SIRT6 is also activated by fatty acids, providing additional metabolite integration.70 Together, these studies suggest that altered glucocorticoid rhythms, feeding patterns, and food type may contribute to functional desynchrony between the master pacemaker and the liver.

Circadian disruption and metabolism

A properly entrained circadian system is central to maintaining metabolic homeostasis; it is therefore not unexpected that poor circadian hygiene alters metabolism. Although clock gene mutations have been associated with obesity, the majority of the population does not possess these mutations. Instead, modern society participates in lifestyles that are incongruent with entrainment to the natural lighting environment.71,72 Disruption of entrainment occurs by shifting work schedules (shift work), travel and social life (physical and social jet lag), food intake (misaligned feeding) late into the night, or exposure to light late into the night (light at night), all of which have been on the rise during the past century and have been associated with adverse health outcomes. In the following sections, experimental, clinical, and epidemiological studies implicating circadian disruption in the global rise in obesity are discussed.

Circadian desynchrony

Experimentally, forced desynchrony exposes an animal to a photoperiod, or day length, longer or shorter than the natural day, or forcibly shifts activity patterns to the inactive phase. Exposure to a 20-hour light/dark cycle, incongruous to the natural 24-hour period, results in increased body mass, hyperleptinemia, and hyperinsulinemia independent of changes in circulating glucocorticoids.73 Chronic phase advances increase body mass, fat mass, adipocyte size, and circulating triglycerides.74 Forced activity during an 8-hour window of the inactive phase increases body mass, flattens glucose rhythms, alters glucose tolerance, shifts the peak in serum triglycerides to the daytime, and overall alters rhythmicity in the hypothalamus and the liver.7577 Nighttime food restriction in rats exposed to this forced activity protocol restores glucose rhythms and baseline body mass.75

Approximately 20% of the global population works in night shifts, forcing individuals to be physically, mentally, and metabolically active out of circadian phase. Shift work has been associated with increased prevalence for obesity, diabetes, systemic inflammation, and other metabolic co-morbidities.7885 Human participants exposed to a forced desynchrony protocol display hyperglycemia, insulin resistance, poor glucose tolerance, increased arterial pressure, and reversed cortisol rhythms when they are ~12 hours out of phase with the environmental light–dark cycle.86 The 12-hour phase shifts also increase blood pressure, C-reactive protein, and inflammatory mediators and decrease vagal tone, all contributing to increased cardiovascular disease risk.87 To replicate the multimodal disruption induced by shift work, Buxton et al subjected healthy adults to a combined sleep restriction and circadian disruption protocol for 3 weeks.88 This challenge reduced metabolic rate and induced postprandial hyperglycemia due to hypoinsulinemia.

Jet lag occurs when a person travels rapidly over multiple time zones leading to a discrepancy between internal time and the external light–dark cycle. People who experience repeated shifts across time zones exhibit increased serum cholesterol.89 Social jet lag, on the other hand, is the discrepancy that occurs between circadian time and social schedules, which results in circadian disruption and often sleep loss. Social jet lag is associated with increased BMI, independent of sleep duration.90 In a cohort of specifically nonshift workers, individuals with higher social jet lag scores (greater discrepancy) had higher BMI and fat mass and were more likely to have metabolic syndrome. Additionally, social jet lag was also associated with indicators of inflammation and diabetes in “metabolically unhealthy” obese participants.91 Delaying bedtime by 8.5 hours for 4 days decreases insulin sensitivity and inflammation.92 Endocrine rhythms, specifically leptin and melatonin, are depressed in night active individuals, defined as having an average sleep onset of 01:30 hours relative to 22:30 hours in control participants.93

Delayed feeding

Food can act as an entraining cue to the liver clock, which has been established as central to metabolic homeostasis. Delayed food consumption or feeding during the inactive phase has been associated with increased weight and metabolic dysfunction. Restriction of feeding to the inactive phase, during the light phase in nocturnal rodents, increases body mass, fat mass, and liver clock gene profile.75,76,94 When compounded with a high-fat diet, mice develop obesity, altered circadian endocrine, and locomotor profiles.60,9597 Restricting high-fat diet consumption to the active phase, in contrast, can protect against reduced clock gene amplitude, weight gain, and metabolic disease.98100

Delayed eating in humans is associated with increased risk of obesity. An extreme example of delayed eating is called night eating syndrome, a clinical manifestation of a shift in nighttime food consumption. Night eating syndrome is defined by nighttime hyperphagia and awakenings to eat. Night eating syndrome is associated with an increased risk of obesity, dampened or phase delayed diurnal endocrine rhythms, and a shift in metabolism toward carbohydrate oxidation suggesting altered metabolic function.101

In otherwise healthy individuals, nighttime eating is associated with increased calorie consumption and weight gain.102 This weight gain phenotype is supported by a shift toward carbohydrate oxidation and away from lipid oxidation, as well as increased low density lipoprotein (LDL), suggesting increased circulating cholesterol.103,104 Nighttime eating also confers postprandial hyperglycemia and hyperinsulinemia and a loss of association between plasma glucose and insulin concentrations.93 In a study on eating patterns, more than a third of food intake occurred after 18:00 hours, with half the participants eating over the course of >14 hours a day.105 Overweight individuals exhibiting this eating patterns reduced weight when food intake was restricted to a self-determined 10-hour window.

Light at night

As mentioned earlier, light is the most potent cue to the circadian system. Exposure to constant light desynchronizes locomotor and temperature rhythms in rodents. Mice exposed to constant light experience increased body mass and impaired glucocorticoid rhythmicity, glucose processing, and insulin sensitivity.94,106 These metabolic alterations are associated with elevated food intake during the inactive phase. Exposure to constant light also causes circadian arrhythmia and desynchronizes SCN neuronal networks.106,107

Nightly exposure to dim white light, in contrast to constant light, does not induce locomotor or glucocorticoid arrhythmicity.94,108 Nonetheless, light levels as low as 5 lux induce changes in central and peripheral clock gene expression. Specifically, amplitude of Bmal1, Per1,2, Cry1,2, and REV-ERB-α gene expression rhythms are dampened in the liver in response to exposure to dim light at night.108 Mice exposed to dim light at night experience increased body and fat mass, as well as impaired glucose processing with no change in locomotor activity.94 Much of this metabolic phenotype is attributed to increased food intake during the inactive phase. Light at night has additive effects on weight gain induced by high-fat diet and contributes to the inflammatory pathology of obesity.109 Much like misaligned feeding models, changes in metabolism are reversed by restricting food intake to the active phase and engaging in locomotor exercise.94,110 Additionally, return to a dark night environment resolves weight gain and glucose tolerance within 3 weeks.111

Among humans, recent epidemiological data have begun drawing a connection between nighttime light exposure and body mass. Over 99% of the population of the United States and Europe are exposed to nighttime light. In a study of 100,000 women in the UK, the chances of obesity increased with elevated levels of exposure to light at night.112 Obesity was assessed by BMI, waist:hip and waist:height ratios, and waist circumference, independent of sleep duration. In elderly individuals, exposure to >3 lux of light was associated with higher body weight, BMI, and waist circumference, as well as hyperlipidemia.113

Sleep restriction

Sleep is strongly regulated by the circadian system, but can also have important feedback effects on circadian functions. Disrupted sleep can impair energy metabolism (reviewed in Laposky et al114), and conversely obesity and leptin deficiency disrupt sleep.115,116 Total sleep restriction does induce changes in metabolism but has paradoxical effects on weight.117,118 Additionally, total sleep restriction alters glucose, triglyceride, and adipokine expression.119 Animal models of shift work employ timed sleep restriction, which increases inactive phase locomotor activity, food intake, and clock gene expression. Mice exposed to timed sleep restriction experience increased body mass, despite impaired gluconeogenesis and decreased circulating triglycerides.120 This phenotype is blunted in mice unable to express Per1/2, suggesting their involvement and the necessity of a functional clock.121

Approximately 30% of adults report short sleep durations (<6 hours per night); the prevalence of people experiencing reduced sleep duration has increased substantially since 1985.122 Short sleep duration has also been associated with increased risk for obesity,123,124 increased BMI, and altered metabolic endocrine profile.125127 Experimental sleep restriction to <5 hours a night increased body mass gain by increasing nighttime intake of calories derived from fat.128 Similar sleep restriction also increases glucose, insulin, cortisol, and leptin, induces insulin resistance in adipocytes, and decreases whole body insulin sensitivity and glucose tolerance, suggesting a functional impairment of carbohydrate ­metabolism.129132 This metabolic endocrine disruption is exacerbated by increased sympathetic tone, and altered circadian rhythm in cortisol secretion, which occurs independent of changes in adrenocorticotropic hormone (ACTH), suggesting a deficit at the adrenal level. 129,133

Conclusion

The past century has been a time of booming advances in technology and industrialization bringing about benefits to productivity, efficiency, safety, and convenience. Unfortunately, this has come at a cost to the signals necessary to maintain circadian and physiological homeostasis. During the past decade, experimental and epidemiological studies have suggested detrimental effects of circadian disruption on lipid and carbohydrate metabolism, obesity, and metabolic dysfunction. Delayed feeding, exposure to light at night, and sleep disruption seem to converge in shift workers, producing the most dramatic increases in obesity in epidemiological studies. Individually, these disruptors are much more commonly experienced in the population and have been tied to metabolic disruption. Data from animal studies offer some insight into the mechanisms that may mediate these changes. At the level of the circadian clock, disruption of synchronizing signals impair entrainment and abolish rhythmic and functional endocrine responses; glucose and insulin become uncoupled or insulin sensitivity is abolished, and leptin and glucocorticoids no longer exhibit rhythms. In addition to central disruption, peripheral clocks lose a functional signal of time of day. Within the liver, a critical organ for maintaining lipid and carbohydrate metabolism, this can eliminate temporal compartmentalization of metabolite production, leading to impaired energy allocation and fat deposition. Circadian disruption also is associated with inflammation, both centrally and in the periphery, further exacerbating associated metabolic and cardiovascular diseases.109,134

Although much research has been conducted associating circadian disruption and obesity, the mechanisms by which these phenomena are linked remain unspecified. It seems that disruption of peripheral clocks, by targeted gene knockouts to the liver or pancreas, dim light at night, and restricted feeding, is sufficient to recapitulate the weight gain and metabolic disruption exemplified in epidemiological data. But central disruption can also play a role in mediating weight gain phenotypes. The disruption in endocrine function can be both downstream of weakened central circadian cues and upstream of peripheral disruption, as exemplified by glucocorticoid secretion. Despite an unclear etiology, many of these models show that metabolic shifts toward obesity can be ameliorated when individuals are returned to conditions of good circadian hygiene; that is, feeding restricted to the active phase, return to dark nights, >8 hours of sleep a night, as well as exercise.

There is now substantial evidence that circadian disruption affects human health. Promoting awareness of circadian biology and the consequences of poor circadian hygiene in both the scientific community and the general public are important for improving human health. Reduction of exposure to short wavelength light (blue) at night is consistent with good circadian hygiene. Obesity rates have also increased among human companion animals and laboratory animals. For example, laboratory animals have inexplicably become obese over the past 30 years.135 Perhaps reducing nighttime light exposure in animal colony rooms (typical sources include glass windows on doors, ventilated racks, etc) could improve lab animal housing conditions and make research outcomes more consistent. Similarly, exposure to their human companions’ nighttime lighting or late feeding times may be contributing to the increasing obesity rates among companion animals.

Future research should establish the pathways through which light exposure alters circadian clock genes and determine the elements of this pathway that are crucial for inflammation and metabolic disruption. Very few clinical studies assessing the effects of nighttime light exposure exist. Future clinical studies should evaluate the effects of different light levels in home environments, as well as nursing homes and hospitals where people may be particularly vulnerable to the negative effects of circadian dysregulation. Development of lighting parameters that do not derange circadian organization is critical for human and nonhuman animal health.

Acknowledgments

YMC was supported by National Institute of Health Training Grant T32DE014320, and RJN was supported by National Science Foundation Grant 11-18792 during the preparation of this review.

Disclosure

The authors report no conflicts of interest in this work.

References

1.

Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA. 2012;307:483–490.

2.

WHO. Global status report on noncommunicable diseases; 2014. Availalbe from: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accesssed May 26, 2016.

3.

Stevens GA, Singh GM, Lu Y, et al. National, regional, and global trends in adult overweight and obesity prevalences. Popul Health Metr. 2012;10:22.

4.

Calle EE, Teras LR, Thun MJ. Obesity and mortality. N Engl J Med. 2005;353:2197–2199.

5.

Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006;355:763–778.

6.

Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings from a national cohort of US adults. Am J Epidemiol. 1997;146:214–222.

7.

Resnick HE, Valsania P, Halter JB, Lin X. Relation of weight gain and weight loss on subsequent diabetes risk in overweight adults. J Epidemiol Community Health. 2000;54:596–602.

8.

Lakka TA, Lakka H-M, Salonen R, Kaplan GA, Salonen JT. Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men. Atherosclerosis. 2001;154:497–504.

9.

Kannel WB, Cupples LA, Ramaswami R, Stokes J 3rd, Kreger BE, Higgins M. Regional obesity and risk of cardiovascular disease; the Framingham study. J Clin Epidemiol. 1991;44:183–190.

10.

Auer J, Weber T, Berent R, et al. Obesity, body fat and coronary atherosclerosis. Int J Cardiol. 2005;98:227–235.

11.

Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23:6365–6378.

12.

Pasquali R, Gambineri A. Metabolic effects of obesity on reproduction. Reprod Biomed Online. 2006;12:542–551.

13.

Catalano PM. Obesity, insulin resistance, and pregnancy outcome. Reproduction. 2010;140:365–371.

14.

Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers, Penninx BW, Zitman FG. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67:220–229.

15.

Onyike CU. Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2003;158:1139–1147.

16.

Wang Y, Beydoun MA, Liang L, Caballero B Kumanyika SK. Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring). 2008;16:2323–2330.

17.

Carmelli D, Cardon LR, Fabsitz R. Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments? Am J Hum Genet. 1994;55:566–573.

18.

Price RA, Gottesman II. Body fat in identical twins reared apart: roles for genes and environment. Behav Genet. 1991;21:1–7.

19.

Papas MA, Alberg AJ, Ewing R, Helzlsouer KJ, Gary TL, Klassen AC. The built environment and obesity. Epidemiol Rev. 2007;29:129–143.

20.

Moore RY. Neural control of the pineal gland. Behav Brain Res. 1995;73:125–130.

21.

Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC. mPer1 and mPer2 are essential for normal resetting of the circadian clock. J Biol Rhythms. 2001;16:100–104.

22.

Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert SM. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron. 1997;19:1261–1269.

23.

Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol Genet. 2006;15 Spec No 2:R271–R277.

24.

Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell. 2002;111:919–922.

25.

Bartness TJ, Song CK, Demas GE. SCN efferents to peripheral tissues: implications for biological rhythms. J Biol Rhythms. 2001;16:196–204.

26.

Larsen PJ, Enquist LW, Card JP. Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. Eur J Neurosci. 1998;10:128–145.

27.

Kalsbeek A, Buijs RM, van Heerikhuize JJ, Arts M, van der Woude TP. Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Res. 1992;580:62–67.

28.

Kalsbeek A, van der Spek R, Lei J, Endert E, Buijs RM, Fliers E. Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis. Mol Cell Endocrinol. 2012;349:20–29.

29.

Tsang AH, Barclay JL, Oster H. Interactions between endocrine and circadian systems. J Mol Endocrinol. 2014;52:R1–R16.

30.

Kalsbeek A, La Fleur S, Van Heijningen C, Buijs RM. Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver. J Neurosci. 2004;24:7604–7613.

31.

Buijs RM, Chun SJ, Niijima A, Romijn HJ, Nagai K. Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J Comp Neurol. 2001;431:405–423.

32.

Bamshad M, Song CK, Bartness TJ. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol. 1999;276:R1569–R1578.

33.

Bamshad M, Aoki VT, Adkison MG, Warren WS, Bartness TJ. Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am J Physiol. 1998;275:R291–R299.

34.

Logan RW, Arjona A, Sarkar DK. Role of sympathetic nervous system in the entrainment of circadian natural-killer cell function. Brain Behav Immun. 2011;25:101–109.

35.

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.

36.

Ueyama T, Krout KE, Nguyen XV, Karpitskiy V, Kollert A, Mettenleiter TC, Loewy AD. Suprachiasmatic nucleus: a central autonomic clock. Nat Neurosci. 1999;2:1051–1053.

37.

Kalsbeek A, Fliers E, Franke AN, Wortel J, Buijs RM. Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology. 2000;141:3832–3841.

38.

Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science. 2001;291:490–493.

39.

Balsalobre A, Brown SA, Marcacci L, et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 2000;289:2344–2347.

40.

Ramsey KM, Yoshino J, Brace CS, et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324:651–654.

41.

Eckel-Mahan K, Sassone-Corsi P. Metabolism control by the circadian clock and vice versa. Nat Struct Mol Biol. 2009;16:462–467.

42.

Akhtar RA, Reddy AB, Maywood ES, et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol. 2002;12:540–550.

43.

Reddy AB, Karp NA, Maywood ES, et al. Circadian orchestration of the hepatic proteome. Curr Biol. 2006;16:1107–1115.

44.

Eckel-Mahan KL, Patel VR, Mohney RP, Vignola KS, Baldi P, Sassone-Corsi P. Coordination of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci U S A. 2012;109:5541–5546.

45.

Panda S, Antoch MP, Miller BH, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109:307–320.

46.

Miller BH, McDearmon EL, Panda S, et al. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci U S A. 2007;104:3342–3347.

47.

Storch K-F, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ. Extensive and divergent circadian gene expression in liver and heart. Nature. 2002;417:78–83.

48.

Adamovich Y, Rousso-Noori L, Zwighaft Z, et al. Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. Cell Metab. 2014;19:319–330.

49.

la Fleur SE, Kalsbeek A, Wortel J, Fekkes ML, Buijs RM. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes. 2001;50:1237–1243.

50.

Rudic RD, McNamara P, Curtis A-M, 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. 2004;2:e377.

51.

Shi S, Ansari TS, McGuinness OP, Wasserman DH, Johnson CH. Circadian disruption leads to insulin resistance and obesity. Curr Biol. 2013;23:372–381.

52.

Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005;308:1043–1045.

53.

Marcheva B, Ramsey KM, Buhr ED,et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466:627–631.

54.

Shimba S, Ogawa T, Hitosugi S, et al. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One. 2011;6:e25231.

55.

Grimaldi B, Bellet MM, Katada S, et al. PER2 controls lipid metabolism by direct regulation of PPARγ. Cell Metab. 2010;12:509–520.

56.

Zhang EE, Liu Y, Dentin R, et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med. 2010;16:1152–1156.

57.

Cho H, Zhao X, Hatori M, et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature. 2012;485:123–127.

58.

Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485:62–68.

59.

Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A. 2009;106:21453–21458.

60.

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. J Clin Invest. 1998;101:1020–1027.

61.

Damiola F. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 2000;14:2950–2961.

62.

Holmes MC, French KL, Seckl JR. Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids. J Neurosci. 1997;17:4056–4065.

63.

Reddy AB, Maywood ES, Karp NA, et al. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology. 2007;45:1478–1488.

64.

Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES, Scribner KA, Smith M. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 1993;14:303–347.

65.

Kohsaka A, Laposky AD, Ramsey KM, et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 2007;6:414–421.

66.

Eckel-Mahan KL, Patel VR, de Mateo S, et al. Reprogramming of the circadian clock by nutritional challenge. Cell. 2013;155:1464–1478.

67.

Masri S, Rigor P, Cervantes M, et al. Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell. 2014;158:659–672.

68.

Nakahata Y, Kaluzova M, Grimaldi B, et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell. 2008;134:329–340.

69.

Asher G, Gatfield D, Stratmann M, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008;134:317–328.

70.

Feldman JL, Baeza J, Denu JM. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J Biol Chem. 2013;288:31350–31356.

71.

Scott EM, Carter AM, Grant PJ. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (Lond). 2008;32:658–662.

72.

Sookoian S, Gemma C, Gianotti TF, Burgueño A, Castaño G, Pirola CJ. Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr. 2008;87:1606–1615.

73.

Karatsoreos IN, Bhagat S, Bloss EB, Morrison JH, McEwen BS. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc Natl Acad Sci U S A. 2011;108:1657–1662.

74.

Casiraghi LP, Alzamendi A, Giovambattista A, Chiesa JJ, Golombek DA. Effects of chronic forced circadian desynchronization on body weight and metabolism in male mice. Physiol Rep. 2016;4:e12743.

75.

Salgado-Delgado R, Angeles-Castellanos M, Saderi N, Buijs RM, Escobar C. Food intake during the normal activity phase prevents obesity and circadian desynchrony in a rat model of night work. Endocrinology. 2010;151:1019–1029.

76.

Salgado-Delgado RC, Saderi N, Basualdo Mdel C, Guerrero-Vargas NN, Escobar C, Buijs RM. Shift work or food intake during the rest phase promotes metabolic disruption and desynchrony of liver genes in male rats. PLoS One. 2013;8:e60052.

77.

Salgado-Delgado R, Nadia S, Angeles-Castellanos M, Buijs RM, Escobar C. In a rat model of night work, activity during the normal resting phase produces desynchrony in the hypothalamus. J Biol Rhythms. 2010;25:421–431.

78.

McMenamin TM. A time to work: recent trends in shift work and flexible schedules. Mon Labor Rev. 2007;130(12):3–15.

79.

Macagnan J, Pattussi MP, Canuto R, Henn RL, Fassa AG, Olinto MT. Impact of nightshift work on overweight and abdominal obesity among workers of a poultry processing plant in southern Brazil. Chronobiol Int. 2012;29:336–343.

80.

Di Lorenzo L, De Pergola G, Zocchetti C, et al. Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry. Int J Obes Relat Metab Disord. 2003;27:1353–1358.

81.

Hansen AB, Stayner L, Hansen J, Andersen ZJ. Night shift work and incidence of diabetes in the Danish Nurse Cohort. Occup Environ Med. 2016;73:262–268.

82.

Puttonen S, Viitasalo K, Härmä M. Effect of shiftwork on systemic markers of inflammation. Chronobiol Int. 2011;28:528–535.

83.

Sookoian S, Gemma C, Fernández Gianotti T, Burgueño A, Alvarez A, González CD, Pirola CJ. Effects of rotating shift work on biomarkers of metabolic syndrome and inflammation. J Intern Med. 2007;261:285–292.

84.

Karlsson B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27 485 people. Occup Environ Med. 2001;58:747–752.

85.

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. 2003;76:424–430.

86.

Scheer FAJL, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106:4453–4458.

87.

Morris CJ, Purvis TE, Hu K, Scheer FAJL. Circadian misalignment increases cardiovascular disease risk factors in humans. Proc Natl Acad Sci U S A. 2016;113:E1402–E1411.

88.

Buxton OM, Cain SW, O’Connor SP, et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med. 2012;4:129ra43.

89.

Ekstrand K, Boström PA, Arborelius M, Nilsson JA, Lindell SE. Cardiovascular risk factors in commercial flight aircrew officers compared with those in the general population. Angiology. 1996;47:1089–1094.

90.

Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol. 2012;22:939–943.

91.

Parsons MJ, Moffitt TE, Gregory AM, Goldman-Mellor S, Nolan PM, Poulton R, Caspi A. Social jetlag, obesity and metabolic disorder: investigation in a cohort study. Int J Obes (Lond). 2015;39:842–848.

92.

Leproult R, Holmback U, Van Cauter E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes. 2014;63:1860–1869.

93.

Qin L-Q, Li J, Wang Y, Wang J, Xu JY, Kaneko T. The effects of nocturnal life on endocrine circadian patterns in healthy adults. Life Sci. 2003;73:2467–2475.

94.

Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ. Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci U S A. 2010;107:18664–18669.

95.

Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW. Circadian timing of food intake contributes to weight gain. Obesity. 2009;17:2100–2102.

96.

Reznick J, Preston E, Wilks DL, Beale SM, Turner N, Cooney GJ. Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats. Biochim Biophys Acta. 2013;1832:228–238.

97.

Yasumoto Y, Hashimoto C, Nakao R, et al. Short-term feeding at the wrong time is sufficient to desynchronize peripheral clocks and induce obesity with hyperphagia, physical inactivity and metabolic disorders in mice. Metabolism. 2016;65:714–727.

98.

Hatori M, Vollmers C, Zarrinpar A, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012;15:848–860.

99.

Haraguchi A, Aoki N, Ohstu T, Ikeda Y, Tahara Y, Shibata S. Controlling access time to a high-fat diet during the inactive period protects against obesity in mice. Chronobiol Int. 2014;31:935–944.

100.

Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014;20:991–1005.

101.

Goel N, Stunkard AJ, Rogers NL, et al. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms. 2009;24:85–94.

102.

Gluck ME, Venti CA, Salbe AD, Krakoff J. Nighttime eating: commonly observed and related to weight gain in an inpatient food intake study. Am J Clin Nutr. 2008;88:900–905.

103.

Gluck ME, Venti CA, Salbe AD, Votruba SB, Krakoff J. Higher 24-h respiratory quotient and higher spontaneous physical activity in nighttime eaters. Obesity (Silver Spring). 2011;19:319–323.

104.

Hibi M, Masumoto A, Naito Y, et al. Nighttime snacking reduces whole body fat oxidation and increases LDL cholesterol in healthy young women. Am J Physiol Regul Integr Comp Physiol. 2013;304:R94–R101.

105.

Gill S, Panda S. A smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 2015;22:789–798.

106.

Coomans CP, van den Berg SA, Houben T, et al. Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity. FASEB J. 2013;27:1721–1732.

107.

Ohta H, Yamazaki S, McMahon DG. Constant light desynchronizes mammalian clock neurons. Nat Neurosci. 2005;8:267–269.

108.

Fonken LK, Aubrecht TG, Meléndez-Fernández OH, Weil ZM, Nelson RJ. Dim light at night disrupts molecular circadian rhythms and increases body weight. J Biol Rhythms. 2013;28:262–271.

109.

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. Endocrinology. 2013;154:3817–3825.

110.

Fonken LK, Meléndez-Fernández OH, Weil ZM, Nelson RJ. Exercise attenuates the metabolic effects of dim light at night. Physiol Behav. 2014;124:33–36.

111.

Fonken LK, Weil ZM, Nelson RJ. Dark nights reverse metabolic disruption caused by dim light at night. Obesity (Silver Spring). 2013;21:1159–1164.

112.

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 100,000 women in the breakthrough generations study. Am J Epidemiol. 2014;180:245–250.

113.

Obayashi K, Saeki K, Iwamoto J, et al. Exposure to light at night, nocturnal urinary melatonin excretion, and obesity/dyslipidemia in the elderly: a cross-sectional analysis of the HEIJO-KYO study. J Clin Endocrinol Metab. 2013;98:337–344.

114.

Laposky AD, Bass J, Kohsaka A, Turek FW. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett. 2008;582:142–151.

115.

Laposky AD, Shelton J, Bass J, Dugovic C, Perrino N, Turek FW. Altered sleep regulation in leptin-deficient mice. Am J Physiol Regul Integr Comp Physiol. 2006;290:R894–R903.

116.

Laposky AD, Bradley MA, Williams DL, Bass J, Turek FW. Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice. Am J Physiol Regul Integr Comp Physiol. 2008;295:R2059–R2066.

117.

Everson CA, Crowley WR. Reductions in circulating anabolic hormones induced by sustained sleep deprivation in rats. Am J Physiol Endocrinol Metab. 2004;286:E1060–E1070.

118.

Vetrivelan R, Fuller PM, Yokota S, Lu J, Saper CB. Metabolic effects of chronic sleep restriction in rats. Sleep. 2012;35:1511–1520.

119.

Rosa Neto JC, Lira FS, Venancio DP, et al. Sleep deprivation affects inflammatory marker expression in adipose tissue. Lipids Health Dis. 2010;9:125.

120.

Barclay JL, Husse J, Bode B, et al. Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork. PLoS One. 2012;7:e37150.

121.

Husse J, Hintze SC, Eichele G, Lehnert H, Oster H. Circadian clock genes Per1 and Per2 regulate the response of metabolism-associated transcripts to sleep disruption. PLoS One. 2012;7:e52983.

122.

Luckhaupt SE, Tak S, Calvert GM. The prevalence of short sleep duration by industry and occupation in the National Health Interview Survey. Sleep. 2010;33:149–159.

123.

Cappuccio FP, Taggart FM, Kandala N-B, Currie A, Peile E, Stranges S, Miller MA. Meta-analysis of short sleep duration and obesity in children and adults. Sleep. 2008;31:619–626.

124.

Patel SR, Hu FB. Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring). 2008;16:643–653.

125.

Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1:e62.

126.

Spiegel, K. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846.

127.

Spiegel K, Leproult R, L’hermite-Balériaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004;89:5762–5771.

128.

Spaeth AM, Dinges DF, Goel N. Effects of experimental sleep restriction on weight gain, caloric intake, and meal timing in healthy adults. Sleep. 2013;36:981–990.

129.

Reynolds AC, Dorrian J, Liu PY, Van Dongen HP, Wittert GA, Harmer LJ, Banks S. Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. PLoS One. 2012;7:e41218.

130.

Broussard JL, Ehrmann DA, Van Cauter E, Tasali E, Brady MJ. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann Intern Med. 2012;157:549–557.

131.

Buxton OM, Pavlova M, Reid EW, Wang W, Simonson DC, Adler GK. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes. 2010;59:2126–2133.

132.

Nedeltcheva AV, Kessler L, Imperial J, Penev PD. Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab. 2009;94:3242–3250.

133.

Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet (London, England). 1999;354:1435–1439.

134.

Fonken LK, Weil ZM, Nelson RJ. Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide. Brain Behav Immun. 2013;34:159–163.

135.

Klimentidis YC, Beasley TM, Lin HY, et al. Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics. Proc Biol Sci. 2011;278:1626–1632.

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