Role of Hypocretin in Metabolic Effects of Sleep Loss

越来越多的动物和人体研究正在确定睡眠时间、体重调节和能量消耗之间的重要相互关系。这项建议的目的是在动物模型中系统地评估慢性部分睡眠限制的代谢和内分泌后果。具体地说，我们打算研究慢性部分睡眠限制对Ghrelin、Leptin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。这些实验将在三个动物模型(大鼠、小鼠、猴子)中进行。我们将使用在大鼠和小鼠身上建立的急性和慢性睡眠剥夺方案，并使其适应于进行慢性睡眠剥夺 在新陈代谢记录室。我们假设，在这些动物模型中，长期睡眠不足会增加食物摄入量，而不是能量消耗，从而导致体重增加。Ghrelin和下丘脑肌素的增加，以及Leptin的减少将参与这些变化的调节。下一步，我们将使用基因敲除模型来测试是否增加的下丘脑泌素活性参与了其中一些变化的调节。我们的假设是，睡眠剥夺期间增加的下丘脑泌素按比例增加的能量消耗比食物摄入量更多。在下丘脑泌素基因敲除小鼠中，部分睡眠剥夺将通过依赖于ghrelin/瘦素但不依赖下丘脑泌素的途径刺激食欲，而不会平衡能量的增加。 支出，导致肥胖。这些研究对于扩大我们对慢性睡眠不足、新陈代谢和体重调节之间的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.