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Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO, were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring. Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. In addition, bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity,but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited.

AIMS/HYPOTHESIS: Insufficient sleep is increasingly recognised as a major risk factor for the development of obesity and diabetes, and short-term sleep loss in clinical studies leads to a reduction in insulin sensitivity. Sleep loss-induced metabolic impairments are clinically relevant, since reductions in insulin sensitivity after sleep loss are comparable to insulin sensitivity differences between healthy individuals and those with impaired glucose tolerance. However, the relative effects of sleep loss vs high-fat feeding in the same individual have not been assessed. In addition, to our knowledge no diurnal (active during the daytime) non-human mammalian model of sleep loss-induced metabolic impairment exists, which limits our ability to study links between sleep and metabolism.METHODS: This study examined the effects of one night of total sleep deprivation on insulin sensitivity and beta cell function, as assessed by an IVGTT, before and after 9 months of high-fat feeding in a canine model.RESULTS: One night of total sleep deprivation in lean dogs impaired insulin sensitivity to a similar degree as a chronic high-fat diet (HFD)(normal sleep: 4.95 ± 0.45 mU-1 l-1 min-1; sleep deprivation: 3.14 ± 0.21 mU-1 l-1 min-1; HFD: 3.74 ± 0.48 mU-1 l-1 min-1; mean ± SEM). Hyperinsulinaemic compensation was induced by the chronic HFD, suggesting adequate beta cell response to high-fat feeding. In contrast, there was no beta cell compensation after one night of sleep deprivation, suggesting that there was metabolic dysregulation with acute sleep loss that, if sustained during chronic sleep loss, could contribute to the risk of type 2 diabetes. After chronic high-fat feeding, acute total sleep deprivation did not cause further impairments in insulin sensitivity (sleep deprivation + chronic HFD: 3.28 mU-1 l-1 min-1).CONCLUSIONS/INTERPRETATION: Our findings provide further evidence that sleep is important for metabolic health and establish a diurnal animal model of metabolic disruption during insufficient sleep.

Chronic sleep loss profoundly impacts health in ways coupled to metabolism; however, much existing literature links sleep and metabolism only on acute timescales. To explore the impact of chronically reduced sleep, we conducted unbiased metabolomics on heads from three Drosophila short-sleeping mutants. Common features included elevated ornithine and polyamines; and lipid, acyl-carnitine, and TCA cycle changes suggesting mitochondrial dysfunction. Biochemical studies of overall, circulating, and excreted nitrogen in sleep mutants demonstrate a specific defect in eliminating nitrogen, suggesting that elevated polyamines may function as a nitrogen sink. Both supplementing polyamines and inhibiting their synthesis with RNAi regulated sleep in control flies. Finally, both polyamine-supplemented food and high-protein feeding were highly toxic to sleep mutants, suggesting their altered nitrogen metabolism is maladaptive. Together, our results suggest polyamine accumulation specifically, and nitrogen stress in general, as potential mechanisms linking chronic sleep loss to adverse health outcomes.

Sleep and metabolism are interconnected homeostatic states; the sleep cycle can be entrained by the feeding cycle, and perturbation of the sleep often results in dysregulation in metabolism. However, the neuro-molecular mechanism by which metabolism regulates sleep is not fully understood. We investigated how metabolism and feeding regulate sleep using satiety quiescence behavior as a readout in Caenorhabditis elegans, which shares certain key aspects of postprandial sleep in mammals. From an RNA interference-based screen of two neuropeptide families, RFamide-related peptides (FLPs) and insulin-like peptides (INSs), we identified flp-11, known to regulate other types of sleep-like behaviors in C. elegans, as a gene that plays the most significant role in satiety quiescence. A mutation in flp-11 significantly reduces quiescence, whereas over-expression of the gene enhances it. A genetic analysis shows that FLP-11 acts upstream of the cGMP signaling but downstream of the TGFβ pathway, suggesting that TGFβ released from a pair of head sensory neurons (ASI) activates FLP-11 in an interneuron (RIS). Then, cGMP signaling acting in downstream of RIS neurons induces satiety quiescence. Among the 28 INSs genes screened, ins-1, known to play a significant role in starvation-associated behavior working in AIA is inhibitory to satiety quiescence. Our study suggests that specific combinations of neuropeptides are released, and their signals are integrated in order for an animal to gauge its metabolic state and to control satiety quiescence, a feeding-induced sleep-like state in C. elegans.

Artificial light at night is constantly minimizing the span of dark nights from the natural light-dark cycle of earth. Over the past century, the "lightscape" of earth has completely changed owing to technological advancements which subsequently changed the lifestyle of human as well as the nearby animal species. This motivated the present study, wherein we investigated the impact of light at night (LAN) on behavior and physiology of a diurnal passerine finch, baya weaver (Ploceus philippinus). A group of bird (N=10) exposed to 12L:12D photoperiod was initially subjected to dark nights (0 lux) for a period of 1.5 weeks followed by 5 lux, night light for a span of 4 weeks. The first week in LAN served as acute treatment with respect to the fourth week (chronic). The results reveal significant increase in nighttime activity and sleep loss with respect to acute LAN, while significant inclusion of drowsiness behavior during the day in response to chronic LAN. Besides these behavioral alterations, changes in physiological parameters such as reduction in body mass, loss of gradient between pre- and post- prandial blood glucose levels, and elevation in plasma corticosterone levels were more prominent during acute exposure of LAN. Plasma metabolites such as triglycerides, total protein, serum glutamic-oxaloacetic transaminase (SGOT), and creatinine concentrations also hiked in response to acute LAN treatment. Thus, acute exposure of LAN seems to serve as a novel environment for the bird leading to more pronounced impacts on behavioral and physiological observations during the experiment. In chronic exposure, the birds sort of adapted themselves to the prevailing circumstances as evident by decreased nighttime activity, rebound of sleep and corticosterone levels, etc. Thus, the study clearly demonstrates the differential impact of acute and chronic exposure of LAN on behavior and physiology of birds.

The regulation of sleep and metabolism are highly interconnected, and dysregulation of sleep is linked to metabolic diseases that include obesity, diabetes, and heart disease. Furthermore, both acute and long-term changes in diet potently impact sleep duration and quality. To identify novel factors that modulate interactions between sleep and metabolic state, we performed a genetic screen for their roles in regulating sleep duration, starvation resistance, and starvation-dependent modulation of sleep. This screen identified a number of genes with potential roles in regulating sleep, metabolism, or both processes. One such gene encodes the auxiliary ion channel UNC79, which was implicated in both the regulation of sleep and starvation resistance. Genetic knockdown or mutation of unc79 results in flies with increased sleep duration, as well as increased starvation resistance. Previous findings have shown that unc79 is required in pacemaker for 24-hours circadian rhythms. Here, we find that unc79 functions in the mushroom body, but not pacemaker neurons, to regulate sleep duration and starvation resistance. Together, these findings reveal spatially localized separable functions of unc79 in the regulation of circadian behavior, sleep, and metabolic function.

A molecular circadian clock exists not only in the brain, but also in most cells of the body. Research over the past two decades has demonstrated that it directs daily rhythmicity of nearly every aspect of metabolism. It also consolidates sleep-wake behavior each day into an activity/feeding period and a sleep/fasting period. Otherwise, sleep-wake states are mostly controlled by hypothalamic and thalamic regulatory circuits in the brain that direct overall brain state. Recent evidence suggests that hypothalamic control of appetite and metabolism may be concomitant with sleep-wake regulation, and even share the same control centers. Thus, circadian control of metabolic pathways might be overlaid by sleep-wake control of the same pathways, providing a flexible and redundant system to modify metabolism according to both activity and environment.

During the last decade, optogenetic-based circuit mapping has become one of the most common approaches to systems neuroscience, and amassing studies have expanded our understanding of brain structures causally involved in the regulation of sleep-wake cycles. Recent imaging technologies enable the functional mapping of cellular activity, from population down to single-cell resolution, across a broad repertoire of behaviors and physiological processes, including sleep-wake states. This chapter summarizes experimental evidence implicating hypocretins/orexins, melanin-concentrating hormone, and inhibitory neurons from the lateral hypothalamus (LH) in forming an intricate network involved in regulating sleep and metabolism, including feeding behaviors. It further confirms the dual sleep-metabolic functions of LH cells, and sheds light on a possible mechanism underlying brain plasticity during sleep and metabolic disorders.

Background and objectives: A time-restricted diet is one of the various ways to improve metabolic condition and weight control. However, until now, there have been few pieces of evidence and research to verify the methods and effectiveness of time-restricted diets on metabolic improvement and health promoting. We designed this study to make a healthy diet program and to verify the effectiveness of a time-restricted diet on general health, including sleep and metabolism, in healthy volunteers. Materials and Methods: This study was conducted in healthy adults who are obese but do not have related metabolic disease. Fifteen participants were recruited. Before and after this program, serologic tests including ketone level, questionnaires&mdash, daytime sleepiness evaluation such as the Epworth sleepiness scale and the Stanford sleepiness scale, the Korean version of the Pittsburgh sleep questionnaire index, STOP BANG to evaluate sleep apnea, the Hospital Anxiety and Depression Scale for emotion/sleep&mdash, and polysomnography (PSG) were conducted to evaluate the effects on sleep of the program. They were divided into two groups based on ketone levels that could reflect the constancy of participation in this study. We analyzed the before and after results of each group. Results: Fifteen participants (nine males and six females) completed this program without significant adverse events. Body weight after this program decreased to 78.2 &plusmn, 14.1 from 82.0 &plusmn, 15.6 kg (p = 0.539), and BMI decreased to 27.9 &plusmn, 3.8 from 29.3 &plusmn, 4.6 kg/m2 (p = 0.233). Weight loss was observed in 14 subjects except 1 participant. The results from questionnaires before and after this were not significant changes. They were classified into high/low-ketone groups according to the ketone level of the participants. In the results of the PSG, the apnea hypopnea index (25.27 &plusmn, 12.67&rarr, 15.11 &plusmn, 11.50/hr, p = 0.25) and oxygen desaturation (18.43 &plusmn, 12.79&rarr, 10.69 &plusmn, 10.0/hr, p = 0.004), which are indicators of sleep apnea, also improved in the high-ketone group, compared with the low-ketone group. Satisfaction interviews for this restricted diet program showed that 86% of the participants were willing to participate in the same program again. Conclusion: The time-restricted diet was successful in weight loss for a period of 4 weeks in obese participants, which did not affect the efficiency and architecture of sleep. In addition, successful weight loss and significant improvement of sleep apnea were showed in the high-ketone group. Further research is needed to demonstrate mechanisms for weight loss, sleep apnea, and time-restricted diets.

Sleep and metabolism are essential components of health. Metabolic health depends largely on individual's lifestyle. Disturbances in sleep health, such as changes in sleep patterns that are associated with menopause/reproductive aging and chronologic aging, may have metabolic health consequences. Sleep restriction and age-related changes in sleep and circadian rhythms may influence changes in appetite and reproductive hormones, energy expenditure, and body adiposity. In this article, the authors describe how menopause-related sleep disturbance may affect eating behavior patterns, immunometabolism, immunometabolic dysfunction, and associations between sleep and metabolic outcomes.

Alzheimer’s disease (AD) is the most common form of dementia and affects over 45 million people worldwide. Both type-2-diabetes (T2D), a metabolic condition associated with aging, and disrupted sleep are implicated in the pathogenesis of AD, but how sleep and metabolism interact to affect AD progression remains unclear. In the healthy brain, sleep/wake cycles are a well-coordinated interaction between metabolic and neuronal activity, but when disrupted, are associated with a myriad of health-related issues, including metabolic syndrome, cardiovascular disease, T2D, and AD. Therefore, this review will explore our current understanding of the relationship between metabolism, sleep, and AD-related pathology to identify the causes and consequences of disease progression in AD. Moreover, sleep disturbances and metabolic dysfunction could serve as potential therapeutic targets to mitigate the increased risk of AD in individuals with T2D or offer a novel approach for treating AD.

Behavioural variant frontotemporal dementia (bvFTD) is a complex and heterogeneous disorder with as yet unidentified unifying pathophysiological mechanism. There is emerging evidence that hypothalamic dysfunction, manifesting as disturbances in sleep and metabolism, is an integral component of neurodegeneration in bvFTD. Although sleep and metabolic disturbances and the behavioural abnormalities of bvFTD may appear disparate on the surface, there may be a common underlying hormonal mechanism involving orexin. Orexin is a hypothalamic neurotransmitter directly responsible for control of sleep and metabolism in healthy individuals and is implicated in many abnormal behaviours commonly seen in bvFTD - such as impulsive behaviour, hedonistic reinforcement and binge-consumption of ethanol. Further characterising orexin's role in pathophysiology of bvFTD could lead to a new paradigm for understanding this disease and may provide a new direction towards effective management and treatment.

Summary A new study in fruit flies identifies a molecule, Eaat2, that regulates both sleep and metabolic rate. Surprisingly, Eaat2 acts in a specific glial subtype to modulate both processes, suggesting a cellular link in the brain between sleep and metabolism.

IN BRIEF Far from a simple absence of wakefulness, sleep is an active, regulated, and metabolically distinct state, essential for health and well-being. In this article, the authors review the fundamental anatomy and physiology of sleep and its regulation, with an eye toward interactions between sleep and metabolism.

Poor sleep quality due to sleep disorders and sleep loss is highly prevalent in the modern society. Underlying mechanisms show that stress is involved in the relationship between sleep and metabolism through hypothalamic–pituitary–adrenal (HPA) axis activation. Sleep deprivation and sleep disorders are associated with maladaptive changes in the HPA axis, leading to neuroendocrine dysregulation. Excess of glucocorticoids increase glucose and insulin and decrease adiponectin levels. Thus, this review provides overall view of the relationship between sleep, stress, and metabolism from basic physiology to pathological conditions, highlighting effective treatments for metabolic disturbances.

Dysregulation of sleep is associated with metabolic diseases, and metabolic rate is acutely regulated by sleep-wake behavior. In humans and rodent models, sleep loss is associated with obesity, reduced metabolic rate, and negative energy balance, yet little is known about the neural mechanisms governing interactions between sleep and metabolism. We have developed a system to simultaneously measure sleep and metabolic rate in individual Drosophila, allowing for interrogation of neural systems governing interactions between sleep and metabolic rate. Like mammals, metabolic rate in flies is reduced during sleep and increased during sleep deprivation suggesting sleep-dependent regulation of metabolic rate is conserved across phyla. The reduction of metabolic rate during sleep is not simply a consequence of inactivity because metabolic rate is reduced ∼30 minutes following the onset of sleep, raising the possibility that CO2 production provides a metric to distinguish different sleep states in the fruit fly. To examine the relationship between sleep and metabolism, we determined basal and sleep-dependent changes in metabolic rate is reduced in starved flies, suggesting that starvation inhibits normal sleep-associated effects on metabolic rate. Further, translin mutant flies that fail to suppress sleep during starvation demonstrate a lower basal metabolic rate, but this rate was further reduced in response to starvation, revealing that regulation of starvation-induced changes in metabolic rate and sleep duration are genetically distinct. Therefore, this system provides the unique ability to simultaneously measure sleep and oxidative metabolism, providing novel insight into the physiological changes associated with sleep and wakefulness in the fruit fly.Significance statementMetabolic disorders are associated with sleep disturbances, yet our understanding of the mechanisms underlying interactions between sleep and metabolism remain limited. Here, we describe a novel system to simultaneously record sleep and metabolic rate in single Drosophila. Our findings reveal that uninterrupted sleep bouts of 30 minutes or greater are associated with a reduction in metabolic rate providing a physiological readout of sleep. Use of this system, combined with existing genetic tools in Drosophila, will facilitate identification of novel sleep genes and neurons, with implications for understanding the relationship between sleep loss and metabolic disease.

Dysregulation of sleep and metabolism has enormous health consequences. Sleep loss is linked to increased appetite and insulin insensitivity, and epidemiological studies link chronic sleep deprivation to obesity-related disorders including type II diabetes and cardiovascular disease. Interactions between sleep and metabolism involve the integration of signaling from brain regions regulating sleep, feeding, and metabolic function. Investigating the relationship between these processes provides a model to address more general questions of how the brain prioritizes homeostatically regulated behaviors. The availability of powerful genetic tools in the fruit fly, Drosophila melanogaster, allows for precise manipulation of neural function in freely behaving animals. There is a strong conservation of genes and neural circuit principles regulating sleep and metabolic function, and genetic screens in fruit flies have been effective in identifying novel regulators of these processes. Here, we review recent findings in the fruit fly that further our understanding of how the brain modulates sleep in accordance with metabolic state.

Reduced sleep duration has been increasingly reported to predict obesity. However, timing and regularity of sleep may also be important. In this study, the cross-sectional association between objectively measured sleep patterns and obesity was assessed in two large cohorts of older individuals. Wrist actigraphy was performed in 3053 men (mean age: 76.4 years) participating in the Osteoporotic Fractures in Men Study and 2985 women (mean age: 83.5 years) participating in the Study of Osteoporotic Fractures. Timing and regularity of sleep patterns were assessed across nights, as well as daytime napping. Greater night-to-night variability in sleep duration and daytime napping were associated with obesity independent of mean nocturnal sleep duration in both men and women. Each 1 h increase in the standard deviation of nocturnal sleep duration increased the odds of obesity 1.63-fold (95% confidence interval: 1.31–2.02) among men and 1.22-fold (95% confidence interval: 1.01–1.47) among women. Each 1 h increase in napping increased the odds of obesity 1.23-fold (95% confidence interval: 1.12–1.37) in men and 1.29-fold (95% confidence interval: 1.17–1.41) in women. In contrast, associations between later sleep timing and night-to-night variability in sleep timing with obesity were less consistent. In both older men and women, variability in nightly sleep duration and daytime napping were associated with obesity, independent of mean sleep duration. These findings suggest that characteristics of sleep beyond mean sleep duration may have a role in weight homeostasis, highlighting the complex relationship between sleep and metabolism.

The anatomical and functional mapping of lateral hypothalamic circuits has been limited by the numerous cell types and complex, yet unclear, connectivity. Recent advances in functional dissection of input-output neurons in the lateral hypothalamus have identified subset of inhibitory cells as crucial modulators of both sleep-wake states and metabolism. Here, we summarize these recent studies and discuss the multi-tasking functions of hypothalamic circuitries in integrating sleep and metabolism in the mammalian brain.

Sleep disturbances are associated with hormonal imbalances and may result in metabolic disorders including obesity and diabetes. Therefore, circuits controlling both sleep and metabolism are likely to play a role in these physiopathological conditions. The hypocretin (Hcrt) system is a strong candidate for mediating both sleep and metabolic imbalances because Hcrt neurons are sensitive to metabolic hormones, including leptin and ghrelin, and modulate arousal and goal-orientated behaviours. This review discusses the role of Hcrt neurons as a sensors of energy balance and arousal and proposes new ways of probing local hypothalamic circuits regulating sleep and metabolism with unprecedented cellular specificity and temporal resolution.

Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock, and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g., obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude-enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep, and metabolism will also have far-reaching implications for various chronic human diseases and aging.

This chapter discusses traditional metabolic genes that contribute to sleep regulation as well as candidate genes that may govern the systems independently. Inadequate sleep simultaneously modulates the level of multiple hormones that govern metabolism. In general, with sleep deprivation, the following hormones are decreased: insulin, growth hormone (GH), growth hormone releasing hormone (GHRH), and leptin levels. Even though starvation appears to confer fewer detrimental effects with extended waking than sleep deprivation, this response may come with consequences of its own. There are increasing number of proteins that affect sleep and metabolism, but are not classical metabolic genes. One class of genes that links metabolism and sleep is the circadian rhythm genes. It is interesting to note how often the effect of sleep deprivation invokes a starvation-like response from the body and how a starvation or a starvation-like state results in decreased sleep.

The reciprocal interaction between the immune system and sleep regulation has been widely acknowledged but the cellular mechanisms that underpin this interaction are not completely understood. In the present study, we investigated the role of macrophages in sleep loss- and cold exposure-induced sleep and body temperature responses. Macrophage apoptosis was induced in mice by systemic injection of clodronate-containing liposomes (CCL). We report that CCL treatment induced an immediate and transient increase in non-rapid-eye movement sleep (NREMS) and fever accompanied by decrease in rapid-eye movement sleep, motor activity and NREMS delta power. Chronically macrophage-depleted mice had attenuated NREMS rebound after sleep deprivation compared to normal mice. Cold-induced increase in wakefulness and decrease in NREMS, rapid-eye movement sleep and body temperature were significantly enhanced in macrophage-depleted mice indicating increased cold sensitivity. These findings provide further evidence for the reciprocal interaction among the immune system, sleep and metabolism, and identify macrophages as one of the key cellular elements in this interplay.

Though occupying up to 30% of our lifetime, the biological process of sleep retains many of its secrets. Most animals need to sleep regularly, but why this is essential for general well-being and life itself remains unknown. One important function of sleep lies in its regulation of metabolic homeostasis. In this chapter we describe the complex interactive relationship of sleep and metabolism and the impact of sleep loss and sleep disruption on the development of the metabolic syndrome. We show that the two processes are regulated by complementary and partially overlapping central circuits and both share a close connection with the circadian clock. In our modern societies sleep hygiene has long been neglected, but it becomes increasingly clear that healthy and sufficient sleep is an essential factor in maintaining a normal body weight and minimizing the risk of developing obesity-associated diseases such as type 2 diabetes and the metabolic syndrome.

Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, β = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, β = 0.076; P

Sleep plays a major role in the regulation of metabolic and endocrine functions. Reproducible changes in the release of pituitary hormones and pituitary-dependent hormones occur during sleep and reflect the interactions between the three sleep regulatory processes, namely the homeostatic, circadian, and ultradian processes. The prevalence of sleep curtailment, obesity, and metabolism-related pathologies is increasing worldwide. Experimental evidence supports an association between sleep shortening and chronic metabolic changes that can lead to obesity and diabetes. Brain circuits regulating both sleep and metabolism may underlie these associations. Sleep curtailment is also suggested to be a chronic stressor that may contribute to increased risk of obesity and metabolic diseases, possibly in part through HPA axis dysregulation. The hypothalamic excitatory neuropeptides, hypocretin/orexin, have potent wake-promoting effects and act to stimulate food intake. These peptides are involved in the interactions between sleep–wake regulation and the neuroendocrine control of appetite. Western lifestyle has major impact on sleep, eating, and activity periods. Growing evidence suggests that this lifestyle, which is accompanied by disrupted biological rhythms, might affect metabolism leading to metabolic morbidities such as obesity and diabetes.

The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.

Sleep and metabolism are intertwined physiologically and behaviorally, but the neural systems underlying their coordination are still poorly understood. The hypothalamus is likely to play a major role in the regulation sleep, metabolism, and their interaction. And increasing evidence suggests that hypocretin cells in the lateral hypothalamus may provide particularly important contributions. Here we review: 1) direct interactions between biological arousal and metabolic systems in the hypothalamus, and 2) indirect interactions between these two systems mediated by stress or reward, emphasizing the role of hypocretins. An increased understanding of the mechanisms underlying these interactions may provide novel approaches for the treatment of patients with sleep disorders and obesity, as well as suggest new therapeutic strategies for symptoms of aging, stress, or addiction.

Why most living organisms participate in sleep remains an enigmatic question. But in recent years, clinical and scientific studies have raised the awareness of the importance of proper sleep to overall health and quality of life. Quality sleep is imperative for the maintenance of good health. People suffering from sleep disturbances are not only fatigued but have impaired memory and learning, increased stress and anxiety, and decreased quality of daily life. While it is clear that sleep homeostasis is influenced by various neuroendocrine systems and pathological conditions, such as feeding, hormonal changes, shifts in light/dark cycles, stress, and infections to name a few, it is not clear how such conditions affect sleep homeostasis. Moreover, this is not a one-way street as neuroendocrine functions are affected by disruptions in sleep; people suffering from sleep disturbances are not only fatigued but also have impaired or dysfunctional neuroendocrine systems that affect the quality of daily life. Thus, the relationship between sleep and neuroendocrinology is an area of intense clinical and scientific interest. Understanding how neuroendocrine mediators affect sleep is central to advancing our understanding of sleep-related disorders. The main focus of this special issue is on current findings and ideas that advance our understanding of the mechanisms underlying the neuroendocrine control of sleep and arousal. The manuscripts submitted to this special issue on sleep and the endocrine brain in the International Journal of Endocrinology center around (1) ovarian hormone control of sleep and women's health, (2) sleep and metabolism, and (3) sleep and stress. While much is known about the mechanics of sleep, the investigation into sex differences and hormonal control of sleep and biological rhythms is in its infancy. Data from a number of species including humans suggest that sex hormones (estrogens, progestins, and androgens) influence the physiology and pathology of sleep and biological rhythms. Women have remained underrepresented in the studies of sleep disorders even though sleep complaints are twice as prevalent in women. In recent years, more sleep studies have included women resulting in exciting findings that are raising more interesting questions. For example, while sleep complaints are generally more frequent in women, objective measures (e.g., polysomnography) suggest that women have better sleep than men. The report by A. Shechter and D.B Boivin reviews the variation in sleep and circadian rhythms at different menstrual phases in healthy women and women with premenstrual dysphoric disorder. The review by M.M. Mahoney discusses the potential consequences of disrupted biological rhythms to female reproductive functions and endocrine profiles. From these reports, it becomes clear that a better understanding of how gonadal hormones influence sleep and rhythms is necessary if we are to gain better knowledge of how dysregulation of endocrine systems influences the mechanisms of sleep and rhythm disorders. The link between sleep loss and metabolic dysfunctions, which potentially underlies the risk for obesity and diabetes mellitus, is growing increasingly stronger. The majority of our submissions call attention to this link between sleep and metabolism. First, S. Sharma and M. Kavuru provide an in-depth overview of the research showing that sleep deprivation and sleep disorders, such as obstructive sleep apnea (OSA), have profound metabolic and cardiovascular implications. Two additional reviews focus on the associations of obstructive sleep apnea with (1) obesity, and neuroendocrine alterations in growth hormone, insulin-like growth factor-I, and the sleep-entrained prolactin rhythm (F. Lanfranco and colleagues) and (2) insulin resistance (S. Bopparaju and S. Surani). Several primary research articles investigating sleep and metabolism also are presented. Sleep duration has been inversely associated with body mass index, and M. -P. St-Onge and colleagues report gender differences in this association with their analysis of data taken from the CARDIA study. Two studies investigating sleep deprivation and glucose metabolism, one in humans and the other in rodents, present similar conclusions that sleep deprivation adversely affects glucose metabolism resulting in an increased risk for the onset of diabetes. The hypothalamo-pituitary-adrenal (HPA) axis that controls the release of the stress hormones (cortisol in primates and corticosterone in rodents) is reciprocally connected to sleep. Sleep damps the HPA activity; however, activation of the HPA axis by a stressor is known to disrupt normal sleep patterns. In this issue, M. Balbo and colleagues discuss the potential consequences of HPA hyperactivity on sleep disturbances and the associated metabolic risks. Similarly, R.B. Machado and colleagues present findings from a rodent model of sleep deprivation that HPA-axis activation negatively impacts on sleep homeostasis. Tumors associated with the hypothalamus-pituitary axis affect endocrine functions. A clinical study by H.L. Muller in this issue reviews the association of increased daytime sleepiness and childhood craniopharyngioma. Our understanding of the neuroendocrine factors influencing sleep and biological rhythms is advancing. Nevertheless, more work is needed to further our understanding about the cellular and molecular mechanisms through which these factors are working. With these advances, therapeutic targets may be elucidated that will help to alleviate the sleep pathologies associated with neuroendocrine dysfunctions. Jessica A. Mong Deborah Suchecki Kazue Semba Barbara L. Parry

Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders may be altering human metabolism.

Association between sleep disturbances and hormonal imbalances can result in metabolic disorders, including obesity and diabetes. The hypothalamus is likely to play a part in these pathophysiological conditions because it contains sleep-wake circuits that are sensitive to metabolic hormones, including leptin and ghrelin. Thus, shared hypothalamic circuits such as the hypocretin and melanin-concentrating hormone systems are strong candidates for mediating both sleep and metabolic imbalances. This review reveals new roles for these systems as sensors and effectors of sleep and wakefulness, and discusses their plasticity in regulating sleep and energy balance. New optical tools that remotely control neuronal circuit activity provide an effective means to understand the cooperativity of shared circuits in regulating hypothalamic functions such as sleep and metabolism.

1. The aim of the present review is to outline: (i) the association between sleep and metabolism; (ii) how sleep duration influences the development of disease; and (iii) how sex differences, ageing and obesity may potentially influence the relationship between sleep, metabolic control and subsequent disease. 2. Sleep is associated with a number of endocrine changes, including a change in insulin action in healthy young individuals. Sleep duration shows a prospective U-shaped relationship with all-cause mortality, cardiovascular disease and Type 2 diabetes. 3. Chronic sleep restriction is becoming more common. Experimental sleep restriction impedes daytime glucose control and increases appetite. 4. The sex hormones oestrogen and testosterone influence sleep duration and quality and may account for sex differences in the prevalence of sleep-related disorders. 5. Ageing is associated with a decreased sleep duration, decreased muscle mass and impaired insulin action. 6. Obesity impairs insulin action and is associated with the incidence and severity of obstructive sleep apnoea. 7. Sleep plays an integral role in metabolic control. Consequently, insufficient sleep may represent a modifiable risk factor for the development of Type 2 diabetes. The challenge ahead is to identify how sex differences, ageing and obesity could potentially influence the relationship between sleep and metabolism.

Chronic sleep debt is becoming increasingly common and affects millions of people in more-developed countries. Sleep debt is currently believed to have no adverse effect on health. We investigated the effect of sleep debt on metabolic and endocrine functions.We assessed carbohydrate metabolism, thyrotropic function, activity of the hypothalamo-pituitary-adrenal axis, and sympathovagal balance in 11 young men after time in bed had been restricted to 4 h per night for 6 nights. We compared the sleep-debt condition with measurements taken at the end of a sleep-recovery period when participants were allowed 12 h in bed per night for 6 nights.Glucose tolerance was lower in the sleep-debt condition than in the fully rested condition (p0.02), as were thyrotropin concentrations (p0.01). Evening cortisol concentrations were raised (p=0.0001) and activity of the sympathetic nervous system was increased in the sleep-debt condition (p0.02).Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.

Ana C Krieger,1 Heekoung Youn,2 Frank Modersitzki,2 Ya-Lin Chiu,1 Linda M Gerber,1 Elizabeth Weinshel,2 Christine R Fielding21Weill Cornell Medical College and New York Presbyterian Hospital, 2New York University School of Medicine and NYU Langone Medical Center, New York, NYBackground: Obstructive sleep apnea is commonly associated with metabolic changes and obesity, and changes in body weight by either medical or surgical approaches have been considered to affect the severity of sleep apnea and appetite-controlling hormones. This prospective study evaluated the effect of weight loss induced by laparoscopic adjustable gastric banding (LAGB) surgery on respiratory disturbance during sleep, oxygen saturation levels, sleep architecture, and leptin and ghrelin levels.Methods: Participants were patients at a university-based medical center surgical weight loss program. All participants with a body mass index > 30 kg/m2 undergoing LAGB surgery for weight reduction were offered the opportunity to participate in the study. Procedures included overnight polysomnography followed by fasting hormone levels at baseline and 12 months postoperatively.Results: Thirty subjects (10 men, 20 women) of mean age 44.0 ± 12.5 years were recruited. At 12 months postoperatively, mean excess weight loss was 44.4% ± 14%. The apnea-hypopnea index decreased from 34.2 ± 35 to 19.0 ± 21.7 events per hour (P < 0.0001), while leptin levels decreased from 24.5 ± 17.42 pg/mL to 11.6 ± 10.6 pg/mL (P = 0.02). Ghrelin levels did not change substantially. Nadir oxygen saturation levels increased from 81% to 84% at 12 months (P = 0.03). Mean oxygen saturation improved and was positively correlated with ghrelin levels at both time points (r = 0.39, P = 0.07, and r = 0.60, P = 0.01).Conclusion: LAGB surgery was associated with 44.4% excess weight loss at 12 months, accompanied by a 33.7% improvement in apnea-hypopnea index as well as a reduction in leptin levels by 31.7% in this group. An association between ghrelin and mean oxygen saturation was seen and deserves further investigation.Keywords: sleep apnea, obesity, bariatric surgery, weight loss, metabolism, leptin, ghrelin, sleep