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

• 批准号: 9135819
• 负责人: Dongsheng Cai
• 金额: $ 24.84万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 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/9135819
• 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; Health; 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; dietary approach; energy balance; feeding; human FRAP1 protein; improved; insight; interest; mouse model; overexpression; prevent; response; success; transcription factor

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（申请人提供）：下丘脑神经元通过感知营养物质来调节能量平衡和体重控制；然而，潜在的分子基础仍不清楚。最近已知缺氧诱导因子 (HIF) 会被含氧量正常的代谢信号激活，我们最近发表的文章表明，下丘脑 HIF2¿/HIF¡ 对葡萄糖做出反应，并且下丘脑神经元中的 HIF 敲除具有强迫性。因此，本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，生理水平的葡萄糖或亮氨酸都会激活下丘脑 HIF2，与饮食诱导的代谢反应存在因果关系。因此，该提议的假设是，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身体活动和产热的形式）代谢控制很重要。这一假设导致预测，虽然下丘脑 HIF 抑制会导致能量失衡和肥胖，但下丘脑 HIF 基因传递可以改善能量平衡，从而抵消饮食肥胖。提出三个具体目标：（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操作对食欲和能量消耗控制（包括饮食引起的自发体力活动和饮食引起的产热）的影响，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抑制或激活对饮食性肥胖的影响。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 通路的分析，以及与各种营养输送相关的下丘脑 HIF 操作模型。该项目的成功可以带来能量平衡控制的新范式和治疗肥胖的新目标。