Hypothalamic HIF in Nutrient Sensing and Metabolic Control

下丘脑 HIF 在营养感应和代谢控制中的作用

基本信息

批准号：
8700876
负责人：
Dongsheng Cai
金额：
$ 42.59万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700876
关键词：
Behavioral Blood Glucose Body Weight Brain region Brown Fat Calories Complex Data Desire for food Diet Disease Energy Metabolism Feeding behaviors Gene Delivery Gene Expression Genes Genetic Glucose Hypothalamic structure Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Individual Inflammation Injection of therapeutic agent Knock-out Knockout Mice Lead Leucine Link Mediating Mediator of activation protein Metabolic Metabolic Control Metabolism Methods Molecular Neurons Nuclear Nutrient Obesity Outcome Pathway interactions Peptides Peripheral Physical activity Physiological Physiology Pro-Opiomelanocortin Process Proteins Publications Reactive Oxygen Species Reducing diet Regulation Reporting Research Role Signal Transduction Sucrose Sympathetic Nervous System Testing Thermogenesis Up-Regulation Weight maintenance regimen Work base detection of nutrient energy balance feeding human FRAP1 protein improved insight interest mouse model overexpression prevent public health relevance response success transcription factor

项目摘要

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.

描述（由适用提供）：能量平衡和体重控制由下丘脑神经元通过感测营养来调节；但是，基本的分子基础仍然不清楚。最近已知低氧诱导因子（HIF）被常氧代谢信号激活，我们最近的出版物表明，下丘脑神经元中对葡萄糖和HIF基因敲除的下丘脑HIF2？ /HIF的反应是观察力的。因此，这项研究的目的是研究下丘脑营养感应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，葡萄糖或亮氨酸的物理水平都激活了下丘脑HIF2。意外地与饮食诱导的代谢反应相关。因此，该提议的假设是下丘脑HIF对于食欲和能量消耗（包括饮食引起的自发的体育活动和热生成的形式），对于饮食引起的代谢控制很重要。这一假设导致预测，尽管下丘脑HIF抑制会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，以抵消饮食对象。提出了三个特定的目的：（1）研究营养对下丘脑HIF和所涉及的分子机制的影响；（2）研究下丘脑HIF操纵对食欲和能量消耗控制（包括饮食引起的自发体育锻炼和饮食引起的热发生）的影响，还研究了分子介体以及交感神经系统导向的生理机制；（3）下丘脑HIF抑制或激活对饮食肥胖的研究。实验方法将显着基于正常小鼠的代谢和行为生理的分析以及HIF途径，以及与各种营养递送有关的下丘脑HIF操作的模型。该项目的成功可以导致能源平衡控制的新范式，并成为治疗肥胖症的新目标。