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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.

Background: Sleep deprivation (SD) is a growing hazard through its effects on metabolism. Orexin is involved in the regulation of both sleep and metabolism. Work on orexin receptors may explain the mechanisms of some hazardous effects of SD. Aim: To test the role of the orexin-1 receptor (OX1R)blocker, SB-334867 in changes of triglycerides and cholesterol metabolisminduced by SD. Method: 72 adult albino rats arranged in 4 equal groups: control, SD, SD-OX1R blocked &SD-DMSO groups. The 3 SD groups are subjected to 8 days of paradoxical SD using the modified multiple platform method. The OX1R blocked group was injected intraperitoneallydaily with a single dose (3 mg/kg/day) of SB-334867 dissolved in 2 ml DMSO and diluted 1:1000. The SD-DMSO group was injected by 2 ml of DMSO diluted 1:1000. Triglycerides and cholesterol levels were measured. Results: Blood triglyceride levels dropped in all groups subjected to SD after the 1stday while the blood cholesterol level dropped in all groups subjected to SD at the 7th or 8th day. In SD-OX1R blocked group showed less drop in blood triglycerides than the other SD groups but the statistically non-significant change in cholesterol level. Conclusion: SD leads to earlier and more drop-in blood triglyceridesthan the drop in cholesterol levels. This can be explained by high metabolism during SD with dependence on triglyceride more than cholesterol. OX1R blocker partially reduces the drop of triglyceride, not cholesterol level indicating that orexin may be involved in the control of triglyceride metabolism but not cholesterol.

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.

Orexins are hypothalamic neuropeptides that regulate several physiological functions, such as appetite, arousal, cognition, stress, sleep and metabolism. Emerging pieces of evidence suggest an orexinergic dysfunction in several neuropsychiatric disorders, including depression, anxiety and addiction. A syndromic overlap between behavioural variant frontotemporal dementia (bvFTD) and several psychiatric disorders was recently demonstrated. Therefore, we analysed cerebrospinal fluid (CSF) orexin A concentrations of 40 bvFTD and 32 non-demented patients, correlating neuropeptide concentrations with several clinical characteristics. A significant increase of orexin A concentrations was found in bvFTD patients when compared to controls (p

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.

Regulation of circadian behavior and physiology by the Drosophila brain clock requires communication from central clock neurons to downstream output regions, but the mechanism by which clock cells regulate downstream targets is not known. We show here that the pars intercerebralis (PI), previously identified as a target of the morning cells in the clock network, also receives input from evening cells. We determined that morning and evening clock neurons have time of day dependent connectivity to the PI, which is regulated by specific peptides as well as by fast neurotransmitters. Interestingly, PI cells that secrete the peptide DH44, and control rest:activity rhythms, are inhibited by clock inputs while insulin-producing cells are activated, indicating that the same clock cells can use different mechanisms to drive cycling in output neurons. Inputs of morning cells to the DILP2+ neurons are relevant for the circadian rhythm of feeding, reinforcing the role of the PI as a circadian relay that controls multiple behavioral outputs. Our findings provide mechanisms by which clock neurons signal to non-clock cells to drive rhythms of behavior.Significance StatementDespite our growing understanding of how the fly clock network maintains free-running rhythms of behavior and physiology, little is known about how information is communicated from the clock network to the rest of the brain to regulate behavior. We identify glutamate and acetylcholine as key neurotransmitters signaling from clock neurons to the pars interecerebralis (PI), a clock output region regulating circadian rhythms of sleep and metabolism. We report a novel link between Drosophila evening clock neurons and the PI, and find that the effect of clock neurons on output neuron physiology varies, suggesting that the same clock cells use multiple mechanisms simultaneously to drive cycling in output neurons.

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.

Mammalian cryptochromes regulate sleep and metabolism as components of the circadian clock. In this issue of Cell Chemical Biology, Miller et al. (2020a) use phenotypic chemical screens to identify selective modulators of two cryptochrome isoforms. Binding specificity depends on conformational patterning of the ligand-binding pocket and a disordered C-terminal domain.

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.

Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in Drosophila melanogaster brains. Genetic mutants of astray (aay), a fly homolog of the rate-limiting phosphoserine phosphatase in serine biosynthesis, displayed reduced starvation-induced sleep suppression. In contrast, a hypomorphic mutation in a serine/threonine-metabolizing enzyme, serine/threonine dehydratase (stdh), exaggerated starvation-induced sleep suppression. Analyses of double mutants indicated that aay and stdh act on the same genetic pathway to titrate serine levels in the head as well as to adjust starvation-induced sleep behaviors. RNA interference-mediated depletion of aay expression in neurons, using cholinergic Gal4 drivers, phenocopied aay mutants, while a nicotinic acetylcholine receptor antagonist selectively rescued the exaggerated starvation-induced sleep suppression in stdh mutants. Taken together, these data demonstrate that neural serine metabolism controls sleep during starvation, possibly via cholinergic signaling. We propose that animals have evolved a sleep-regulatory mechanism that reprograms amino acid metabolism for adaptive sleep behaviors in response to metabolic needs.

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.

STUDY OBJECTIVES: The rise in obesity has been paralleled by a decline in sleep duration in epidemiological studies. However, the potential mechanisms linking energy balance and the sleep/wake cycle are not well understood. We aimed to examine the effects of manipulating energy balance on the sleep/wake cycle. METHODS: Twelve healthy normal weight men were housed in a clinical research facility and studied at three time points: baseline, after energy balance was disrupted by 2 days of caloric restriction to 10% of energy requirements, and after energy balance was restored by 2 days of ad libitum/free feeding. Sleep architecture, duration of sleep stages, and sleep-associated respiratory parameters were measured by polysomnography. RESULTS: Two days of caloric restriction significantly increased the duration of deep (stage 4) sleep (16.8% to 21.7% of total sleep time; P = 0.03); an effect which was entirely reversed upon free feeding (P = 0.01). Although the apnea-hypopnea index stayed within the reference range (< 5 events per hour), it decreased significantly from caloric restriction to free feeding (P = 0.03). Caloric restriction was associated with a marked fall in leptin (P < 0.001) and insulin levels (P = 0.002). The fall in orexin levels from baseline to caloric restriction correlated positively with duration of stage 4 sleep (Spearman rho = 0.83, P = 0.01) and negatively with the number of awakenings in caloric restriction (Spearman rho = -0.79, P = 0.01). CONCLUSIONS: We demonstrate that changes in energy homeostasis directly and reversibly impact on the sleep/wake cycle. These findings provide a mechanistic framework for investigating the association between sleep duration and obesity risk.

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.

The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation.

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 length and metabolic dysfunction are correlated, but the causal relationship between these processes is unclear. Octopamine promotes wakefulness in the fly by acting through the insulin-producing cells (IPCs) in the fly brain. To determine if insulin signaling mediates the effects of octopamine on sleep:wake behavior, we assayed flies in which insulin signaling activity was genetically altered. We found that increasing insulin signaling does not promote wake, nor does insulin appear to mediate the wake-promoting effects of octopamine. Octopamine also affects metabolism in invertebrate species, including, as we show here, Drosophila melanogaster. Triglycerides are decreased in mutants with compromised octopamine signaling and elevated in flies with increased activity of octopaminergic neurons. Interestingly, this effect is mediated at least partially by insulin, suggesting that effects of octopamine on metabolism are independent of its effects on sleep. We further investigated the relative contribution of metabolic and sleep phenotypes to the starvation response of flies with altered octopamine signaling. Hyperactivity (indicative of foraging) induced by starvation was elevated in octopamine receptor mutants, despite their high propensity for sleep, indicating that their metabolic state dictates their behavioral response under these conditions. Moreover, flies with increased octopamine signaling do not suppress sleep in response to starvation, even though they are normally hyper-aroused, most likely because of their high triglyceride levels. Together, these data suggest that observed correlations between sleep and metabolic phenotypes can result from shared molecular pathways rather than causality, and environmental conditions can lead to the dominance of one phenotype over the other.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Today, the clinical diagnosis of the disease requires unequivocal signs of typical motor disturbances, which is thought to be due to pathology in the striatum of the basal ganglia. Increasing numbers of studies have emphasized that also non-motor symptoms and signs are common and occur early in HD. These include psychiatric disturbances and cognitive impairment as well as sleep disturbances with disrupted circadian rhythm, autonomic dysfunction and metabolic changes. Several of the non-motor features may be results of dysfunction of the hypothalamus and the limbic system, which are interconnected structures central in the regulation of emotion, sleep and metabolism. In fact, recent studies using postmortem tissue, magnetic resonance imaging and positron emission tomography have shown that hypothalamic and limbic system changes occur early in clinical HD. This review summarizes the current state of knowledge in this area based on clinical studies as well as experiments in animal models of the disease and establishes that hypothalamic and limbic system changes are part of the HD pathology.

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although it is characterized by progressive motor impairments, cognitive changes and psychiatric disturbances are major components of the disease. In addition, recent studies have shown that other non-motor symptoms such as alterations in sleep pattern, disruption of the circadian rhythm and increased energy metabolism are common and occur early. Emerging evidence suggests that the latter symptoms are likely results of disturbed functions of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Whereas clinical data are essential to define key pathological features of HD, animal models that can recapitulate the neurobiological and behavioral features of the disorder are critical tools to elucidate the underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine alterations as well as in highlighting novel potential disease pathways. This review summarizes the current state of knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical relevance and points to future implications for this emerging field.

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.

Study objectives Cross-sectional studies report a correlation between slow wave sleep (SWS) duration and insulin sensitivity (SI) in children and adults. Suppression of SWS causes insulin resistance in adults but effects in children are unknown. This study was designed to determine the effect of SWS fragmentation on SI in children. Methods Fourteen pubertal children (11.3-14.1 y, body mass index 29(th) to 97(th) percentile) were randomized to sleep studies and mixed meal (MM) tolerance tests with and without SWS disruption. Beta-cell responsiveness (Φ) and SI were determined using oral minimal modeling. Results During the disruption night, auditory stimuli (68.1 ± 10.7/night; mean ± standard error) decreased SWS by 40.0 ± 8.0%. SWS fragmentation did not affect fasting glucose (non-disrupted 76.9 ± 2.3 versus disrupted 80.6 ± 2.1 mg/dL), insulin (9.2 ± 1.6 versus 10.4 ± 2.0 μIU/mL), or C-peptide (1.9 ± 0.2 versus 1.9 ± 0.1 ng/mL) levels and did not impair SI (12.9 ± 2.3 versus 10.1 ± 1.6 10(-4) dL/kg/min per μIU/mL) or Φ (73.4 ± 7.8 versus 74.4 ± 8.4 10(-9) min(-1)) to a MM challenge. Only the subjects in the most insulin-sensitive tertile demonstrated a consistent decrease in SI after SWS disruption. Conclusion Pubertal children across a range of body mass indices may be resistant to the adverse metabolic effects of acute SWS disruption. Only those subjects with high SI (i.e., having the greatest "metabolic reserve") demonstrated a consistent decrease in SI. These results suggest that adolescents may have a unique ability to adapt to metabolic stressors, such as acute SWS disruption, to maintain euglycemia. Additional studies are necessary to confirm that this resiliency is maintained in settings of chronic SWS disruption.

STUDY OBJECTIVES To investigate the cross-sectional relationship between objectively measured sleep characteristics and multiple indices of adiposity in racially/ethnically diverse older adults within the MESA Sleep study (n = 2,146). METHODS 7-day actigraphy was used to assess sleep duration, sleep efficiency, and night-to-night variability. Body mass index (BMI), waist circumference, and total body fat were modeled continuously and according to obesity cut-points. Models were adjusted for demographic, socioeconomic, and behavioral variables. RESULTS Participants who slept less than 6 hours a night had significantly higher BMI, waist circumference, and body fat relative to those who slept 7-8 hours. Those who slept less than 5 hours had a 16% higher prevalence of general obesity (BMI ≥ 30 vs. < 25 kg/m(2)) (95% [CI]: 0.08-0.24) and a 9% higher prevalence of abdominal obesity (waist circumference: women ≥ 88 centimeters, men ≥ 102 centimeters; 95% CI: 0.03-0.16) compared to those who slept 7-8 hours. Results were similar for sleep efficiency and night-to-night sleep variability. CONCLUSIONS Among an older multi-ethnic cohort, we found robust associations across multiple indices of sleep and adiposity. Targeting sleep characteristics may be of benefit in obesity interventions, but more research is needed to rule out reverse causality.

International audience; Sleep-active neurons located in the ventrolateral preoptic nucleus (VLPO) play a crucial role in the induction and maintenance of slow-wave sleep (SWS). However, the cellular and molecular mechanisms responsible for their activation at sleep onset remain poorly understood. Here, we test the hypothesis that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons. We find that infusion of a glucose concentration into the VLPO of mice promotes SWS and increases the density of c-Fos-labeled neurons selectively in the VLPO. Moreover, we show in patch-clamp recordings from brain slices that VLPO neurons exhibiting properties of sleep-promoting neurons are selectively excited by glucose within physiological range. This glucose-induced excitation implies the catabolism of glucose, leading to a closure of ATP-sensitive potassium (KATP) channels. The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status. Together, these results provide evidence that glucose may participate in the mechanisms of SWS promotion and/or consolidation.SIGNIFICANCE STATEMENT:Although the brain circuitry underlying vigilance states is well described, the molecular mechanisms responsible for sleep onset remain largely unknown. Combining in vitro and in vivo experiments, we demonstrate that glucose likely contributes to sleep onset facilitation by increasing the excitability of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO). We find here that these neurons integrate energetic signals such as ambient glucose directly to regulate vigilance states accordingly. Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the fundamental and intimate link between sleep and metabolism.

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.

Sleep is greatly affected by changes in metabolic state. A possible mechanism where energy-sensing and sleep-regulatory functions overlap is related to lipid metabolism. Fatty acid synthase (FAS) plays a central role in lipid metabolism as a key enzyme in the formation of long-chain fatty acids. We studied the effects of systemic administration of C75, an inhibitor of FAS, on sleep, behavioral activity and metabolic parameters in mice. Since the effects of C75 on feeding and metabolism are the opposite of ghrelin's and C75 suppresses ghrelin production, we also tested the role of ghrelin signaling in the actions of C75 by using ghrelin receptor knockout (KO) mice. After a transient increase in wakefulness, C75 elicited dose-dependent and long lasting inhibition of REMS, motor activity and feeding. Simultaneously, C75 significantly attenuated slow-wave activity of the electroencephalogram. Energy expenditure, body temperature and respiratory exchange ratio were suppressed. The diurnal rhythm of feeding was completely abolished by C75. There was significant correlation between the anorectic effects, the decrease in motor activity and the diminished energy expenditure after C75 injection. We found no significant difference between wild-type and ghrelin receptor KO mice in their sleep and metabolic responses to C75. The effects of C75 resemble to what was previously reported in association with visceral illness. Our findings suggest that sleep and metabolic effects of C75 in mice are independent of the ghrelin system and may be due to its aversive actions in mice.

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.

Huntington's disease (HD) is neither a fatal hereditary neurodegenerative disorder without satisfactory treatments nor a cure. It is caused by a CAG repeat expansion in the huntingtin gene. The clinical symptoms involve motor-, cognitive- and psychiatric disturbances. Recent studies have shown that non-motor symptoms and signs, such as mood changes, sleep disturbances and metabolic alterations often occur before the onset of overt motor impairments. The hypothalamus is one of the main regulators of emotion, sleep and metabolism, and it is therefore possible that dysfunction of the hypothalamus and neuroendocrine circuits may, at least partly, be responsible for these non-motor symptoms in HD. Several hypothalamic and neuroendocrine changes have now been identified in clinical HD as well as in rodent models of the disease. These changes could be important both in the pathogenesis of HD, constitute biomarkers to track disease progression as well as to provide novel therapeutic targets for this devastating disease. The current state of knowledge in the area of hypothalamic and neuroendocrine changes in both patients and rodent models of HD is summarized in this review, and their potential as targets for novel treatment paradigms are discussed.