Role of Hypocretin in Metabolic Effects of Sleep Loss

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A growing number of animal and human studies are identifying important interrelationships between sleep amounts, body weight regulation and energy expenditure. The goal of this proposal is to systematically evaluate the metabolic and endocrine consequences of chronic partial sleep restriction in animal models. Specifically, we intend to examine the effects of chronic partial sleep restriction on the interaction between ghrelin, leptin and hypocretin and on the regulation of body weight and energy expenditure. These experiments will be conducted in three animal models (rat, mouse, monkey). We will use acute and chronic sleep deprivation protocols established in rats and mice and adapt them to conduct chronic sleep deprivation in metabolic recording chambers. We hypothesize that in these animal models chronic sleep deprivation will increase food intake more than energy expenditure, resulting in weight gain. Increased ghrelin and hypocretin, together with decreased leptin will be involved in mediating these changes. We will next test if increased hypocretin activity is involved in mediating some of these changes using knockout models. Our hypothesis is that increased hypocretin during sleep deprivation increases energy expenditure proportionally more than food intake. In hypocretin knockout mice, partial sleep deprivation will stimulate appetite through ghrelin/leptin-dependent, but hypocretin-independent pathway, without a counterbalanced increase in energy expenditure, resulting in obesity. These studies will be critical to extend our understanding of the association between chronic sleep loss, metabolism and body weight regulation.