Exercise and energy balance: role of hypothalamic transthyretin

运动和能量平衡：下丘脑运甲状腺素蛋白的作用

• 批准号: 8147753
• 负责人: SHENG BI
• 金额: $ 33.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-23 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147753
• 关键词: Affect; Anorexia; Body Composition; Body Weight; Body Weight decreased; Brain; Clinical Research; Data; Dependovirus; Desire for food; Development; Diabetes Mellitus; Diet; Eating; Energy Metabolism; Enzymes; Exercise; FOS gene; Fatty acid glycerol esters; Food Energy; Gene Expression; Genetic; Goals; Homeostasis; Hypothalamic structure; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Knock-out; Knowledge; Mediating; Mediation; Modeling; Mus; Nerve; Neurobiology; Neuropeptides; Obesity; Overweight; Patients; Pattern; Peptides; Peripheral; Physical activity; Play; Polymerase Chain Reaction; Prealbumin; Prevention; Process; Proteins; Proteomics; RNA Interference; Rattus; Recombinants; Reporting; Reverse Transcription; Rodent; Role; Running; Signal Pathway; Site; System; Testing; Time; Viral; Work; adeno-associated viral vector; base; combat; design; dietary control; energy balance; feeding; food restriction; improved; knock-down; mRNA Differential Displays; mRNA Expression; neurochemistry; neuromechanism; neuropeptide Y; novel; obesity treatment; overexpression; peptidylglycine alpha-amidating monooxygenase; prevent; public health relevance; recombinant viral vector; relating to nervous system; research study; response; small hairpin RNA; success; vector; weight maintenance

DESCRIPTION (provided by applicant): Exercise or physical activity has long been reported to play a major role in the control of body weight. A number of clinical studies have shown that whereas physical inactivity contributes to the development of obesity, exercise improves weight loss and, added to dietary control, becomes a key factor for success in long- term weight maintenance in overweight and obese patients. Recent work with rodent obesity models has shown that exercise affects energy balance not only by increasing energy expenditure, but also by altering appetite and reducing food intake. Despite these demonstrated effects of exercise, how exercise affects food intake and body weight remains poor understood. The long-term goal of this project is to identify the neural mechanisms underlying the effects of exercise on energy balance. The hypothalamus plays a central role in maintaining energy homeostasis. To identify hypothalamic factors that mediate exercise-induced alterations in food intake and body weight, we have examined hypothalamic gene expression in response to running wheel activity using microarray analyses. These analyses have shown that transthyretin (TTR) gene expression is induced in the dorsomedial hypothalamus (DMH) of exercised rats. We have also shown that central injection of TTR inhibits food intake. Based on these data and the prior observation that TTR knockout results in increased neuropeptide Y levels in mouse peripheral and central nerve systems, we hypothesize that brain TTR may be a major contributing factor to the effects of exercise on food intake and energy balance, and together with other peptides, plays an important role in energy homeostasis. We propose two specific aims to test this hypothesis. Specific Aim 1 will identify the role of brain TTR in the control of energy balance using multiple approaches at neurochemical, pharmacological, genetic and protein levels. Specific Aim 2 will ascertain the target sites and mechanisms of actions of brain TTR in the control of energy balance by gene expression determination and proteomic analysis. Overall, the findings from this proposal will not only advances our understanding of the neurobiological impact of exercise on energy balance, but also provide a potential target for combating obesity. PUBLIC HEALTH RELEVANCE: This proposed project is aimed at identifying the neural mechanisms underlying the effects of exercise on energy balance. Such identification will provide a potential target for the prevention and treatment of obesity.

描述(由申请人提供)：长期以来，锻炼或体力活动一直被报道在控制体重方面起着重要作用。许多临床研究表明，虽然缺乏运动有助于肥胖的发展，但运动可以改善体重减轻，再加上饮食控制，成为超重和肥胖患者成功长期保持体重的关键因素。最近对啮齿动物肥胖模型的研究表明，运动不仅通过增加能量消耗，还通过改变食欲和减少食物摄入量来影响能量平衡。尽管运动的这些效果已得到证实，但运动如何影响食物摄入量和体重仍然知之甚少。该项目的长期目标是确定运动对能量平衡影响的神经机制。下丘脑在维持能量平衡方面起着核心作用。为了确定影响运动引起的食物摄入量和体重变化的下丘脑因素，我们使用微阵列分析检测了下丘脑基因表达对转轮活动的反应。这些分析表明，运动大鼠下丘脑背内侧核(DMH)诱导了反式甲状腺激素(TTR)基因的表达。我们还表明，中枢注射TTR抑制了食物的摄入。根据这些数据和先前观察到的TTR基因敲除导致小鼠周围和中枢神经系统神经肽Y水平升高的观察，我们推测脑TTR可能是运动对食物摄取和能量平衡影响的主要因素，并与其他多肽一起在能量平衡中发挥重要作用。我们提出了两个具体的目标来检验这一假设。具体目标1将在神经化学、药理学、遗传学和蛋白质水平上使用多种方法确定大脑TTR在控制能量平衡中的作用。通过基因表达测定和蛋白质组学分析，确定脑TTR在调节能量平衡中的靶点和作用机制。总体而言，这项提案的发现不仅将增进我们对运动对能量平衡的神经生物学影响的理解，还将为抗击肥胖提供一个潜在的靶点。 与公共健康相关：这项拟议的项目旨在确定运动对能量平衡影响的神经机制。这种识别将为预防和治疗肥胖症提供一个潜在的目标。