Role of Hypocretin in Metabolic Effects of Sleep Loss

越来越多的动物和人类研究正在确定睡眠量，体重调节和能量消耗之间的重要相互关系。该建议的目标是系统地评估动物模型中慢性部分睡眠限制的代谢和内分泌后果。具体而言，我们打算研究慢性部分睡眠限制对生长激素释放肽，瘦素和下丘脑泌素之间的相互作用，以及对体重和能量消耗的调节的影响。这些实验将在三种动物模型（大鼠、小鼠、猴）中进行。我们将使用在大鼠和小鼠中建立的急性和慢性睡眠剥夺协议，并将其用于进行慢性睡眠剥夺 在代谢记录室里。我们假设，在这些动物模型中，慢性睡眠剥夺会增加食物摄入量而不是能量消耗，导致体重增加。生长激素释放肽和下丘脑泌素的增加，以及瘦素的减少将参与介导这些变化。下一步我们将使用基因敲除模型测试下丘脑泌素活性的增加是否参与介导这些变化。我们的假设是，在睡眠剥夺期间增加的下丘脑泌素比食物摄入量更能成比例地增加能量消耗。在下丘脑泌素基因敲除小鼠中，部分睡眠剥夺将通过ghrelin/leptin依赖性但不依赖于下丘脑泌素的途径刺激食欲，而没有能量的平衡增加 支出，导致肥胖。这些研究对于扩展我们对慢性睡眠不足，新陈代谢和体重调节之间关系的理解至关重要。

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.