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：
9238767
负责人：
Dongsheng Cai
金额：
$ 42.59万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
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/9238767
关键词：
Behavioral Blood Glucose Body Weight Brain region Brown Fat Calories Complex Data Desire for food Diet Disease Energy Metabolism FOXO1A gene FRAP1 gene Feeding behaviors Gene Delivery Gene Expression Genes Genetic Glucose Hypothalamic structure Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Impairment 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 Pathologic 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 dietary approach energy balance feeding improved insight interest mouse model obesogenic 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（由申请人提供）：能量平衡和体重控制是由下丘脑神经元通过感知营养物质来调节的；然而，近来已知缺氧诱导因子（HIF）是由常氧代谢激活的。我们最近发表的文章表明，下丘脑 HIF2�/HIF� 对葡萄糖有反应，并且下丘脑神经元中的 HIF 敲除具有强迫性。研究下丘脑营养感应机制及其在代谢生理学或疾病中的重要性，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均激活下丘脑 HIF2，与饮食诱导的代谢反应存在因果关系。提议认为，下丘脑 HIF 对于饮食诱导的食欲和能量消耗（包括饮食诱导的自发体力活动和生热的形式）代谢控制很重要。抑制导致能量失衡和肥胖，下丘脑HIF基因传递可以改善能量平衡以对抗饮食性肥胖，提出三个具体目标：（1）研究营养素对下丘脑HIF的影响及其相关分子机制；（2）研究营养对下丘脑HIF的影响。下丘脑HIF操纵在食欲和能量消耗控制（包括饮食诱导的自发身体活动和饮食诱导的产热）中的作用，并研究分子介质和交感神经系统定向的生理机制（3）研究下丘脑 HIF 对饮食性肥胖的抑制或激活实验方法将主要基于对正常小鼠的代谢和行为生理学以及 HIF 途径的分析，以及与各种营养输送相关的下丘脑 HIF 操作的模型可以导致该项目的成功。能量平衡控制的新范式和治疗肥胖的新目标。