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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.