Hypothalamic HIF in Nutrient Sensing and Metabolic Control

描述（申请人提供）：下丘脑神经元通过感知营养物质调节能量平衡和体重控制；然而，潜在的分子基础仍然很不清楚。缺氧诱导因子（Hypoxia-inducible factor， HIF）最近被发现可以被常氧代谢信号激活，我们最近的研究表明下丘脑HIF2¿/HIF¿对葡萄糖有反应，而下丘脑神经元中HIF的敲除是强迫性的。因此，本研究的目的是研究下丘脑营养感知机制及其在代谢生理或疾病中的重要性。我们最近的初步研究进一步表明，葡萄糖或亮氨酸的生理水平都激活了下丘脑HIF2 -，与饮食诱导的代谢反应有因果关系。因此，该提议的假设是下丘脑HIF在食欲和能量消耗（包括饮食诱导的自发身体活动和产热形式）方面对饮食诱导的代谢控制很重要。这一假设可以预测，下丘脑HIF抑制会导致能量失衡和肥胖，而下丘脑HIF基因传递可以改善能量平衡，抵消饮食性肥胖。本文提出以下三个具体目标：(1)研究营养物质对下丘脑HIF的影响及其分子机制；(2)研究下丘脑HIF操纵在食欲和能量消耗控制中的作用（包括饮食诱导的自发体力活动和饮食诱导的产热），并研究分子介质和交感神经系统引导的生理机制；(3)研究下丘脑HIF抑制或激活对饮食性肥胖的影响。实验方法将主要基于正常小鼠的代谢和行为生理学以及HIF通路的分析，以及下丘脑HIF操作与各种营养输送相关的模型。该项目的成功将为能量平衡控制提供一个新的范例，并为肥胖治疗提供一个新的目标。

DESCRIPTION (provided by applicant): Energy balance and body weight control are regulated by hypothalamic neurons through sensing nutrients; however, the underlying molecular basis is still much unclear. Hypoxia-inducible factor (HIF) has recently been known to be activated by normoxic metabolic signals, and our recent publication showed that hypothalamic HIF2¿/HIF¿ responds to glucose and HIF knockout in hypothalamic neurons are obssogenic. Therefore, the objective of this research is to study hypothalamic nutrient-sensing mechanism and its importance in metabolic physiology or disease. Our recent preliminary studies further revealed that physiological levels of glucose or leucine both activated hypothalamic HIF2¿ to be causally associated with diet-induced metabolic responses. Hence, the hypothesis of this proposal is that hypothalamic HIF is important for diet-induced metabolic control in terms of appetite and energy expenditure (including the forms of diet-induced spontaneous physical activity and thermogenesis). This hypothesis leads to prediction that while hypothalamic HIF inhibition causes energy imbalance and obesity, hypothalamic HIF gene delivery can improve energy balance to counteract dietary obesity. Three Specific Aims are propsoed to: (1) study the effects of nutrients on hypothalamic HIF and the involved molecular mechanism; (2) study the effects of hypothalamic HIF manipulations in appetite and energy expenditure control (including diet-induced spontaneous physical activity and diet-induced thermogenesis), and also study the molecular mediators and the sympathetic nervous system-directed physiological mechanism; (3) study effects of hypothalamic HIF inhibition or activation on dietary obesity. Experimental approaches will be significantly based on analyses of metabolic and behavioral physiology as well as HIF pathway in normal mice and the models with hypothalamic HIF manipulations in relation with various nutrient deliveries. Success of this project can lead to a new paradigm of energy balance control and a new target for treating obesity.