Exercise and Energy Balance: Role of Hypothalamic Transthyretin

描述（由申请人提供）：长期以来，运动或体育活动一直被报道在控制体重方面发挥重要作用。许多临床研究表明，缺乏体育活动会导致肥胖，而运动有助于减肥，加上饮食控制，成为超重和肥胖患者长期成功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来影响能量平衡，还通过改变食欲和减少食物摄入来影响能量平衡。尽管有这些运动的效果，但运动如何影响食物摄入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。下丘脑在维持能量稳态中起着核心作用。为了确定介导运动引起的食物摄入和体重变化的下丘脑因素，我们使用微阵列分析检查了下丘脑基因表达对跑步轮活动的响应。这些分析表明，运动大鼠下丘脑背内侧（DMH）诱导转甲状腺素（TTR）基因表达。我们还表明，中枢注射TTR抑制食物摄入。基于这些数据和先前观察到的TTR敲除导致小鼠外周和中枢神经系统神经肽Y水平升高，我们假设脑TTR可能是运动对食物摄入和能量平衡影响的主要因素，并与其他肽一起在能量稳态中起重要作用。我们提出两个具体目标来检验这一假设。特异性目标1将通过神经化学、药理学、遗传和蛋白质水平的多种方法确定脑TTR在能量平衡控制中的作用。特异性目的2将通过基因表达测定和蛋白质组学分析确定脑TTR在控制能量平衡中的作用靶点和机制。总的来说，这项提议的发现不仅将推进我们对运动对能量平衡的神经生物学影响的理解，而且还为对抗肥胖提供了一个潜在的目标。

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.