Hypothalamic HIF in Nutrient Sensing and Metabolic Control

描述（由申请人提供）：能量平衡和体重控制由下丘脑神经元通过感知营养物质进行调节;然而，潜在的分子基础仍不清楚。低氧诱导因子（HIF）最近被认为是由常氧代谢信号激活的，我们最近的出版物表明，下丘脑HIF 2/HIF对葡萄糖有反应，并且下丘脑神经元中的HIF敲除是致盲的。因此，本研究的目的是探讨下丘脑的营养感受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，生理水平的葡萄糖或亮氨酸都激活了下丘脑HIF 2？，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对于饮食诱导的代谢控制在食欲和能量消耗方面（包括饮食诱导的自发身体活动和产热的形式）是重要的。这一假设导致预测，虽然下丘脑HIF抑制导致能量失衡和肥胖，但下丘脑HIF基因递送可以改善能量平衡以对抗饮食性肥胖。本研究的主要目的是：（1）研究营养素对下丘脑HIF的影响及其分子机制;（2）研究下丘脑HIF调控对食欲和能量消耗的影响（包括饮食诱导的自发性体力活动和饮食诱导的产热），并研究其分子介质和交感神经系统介导的生理机制;（3）研究下丘脑HIF抑制或激活对饮食性肥胖的影响。实验方法将显著基于对正常小鼠的代谢和行为生理学以及HIF通路的分析以及与各种营养输送相关的下丘脑HIF操纵的模型。该项目的成功可能会导致能量平衡控制的新范式和治疗肥胖的新目标。

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.