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着重要作用。许多临床研究表明，尽管缺乏身体活动会导致肥胖症的发展，但运动可以改善体重减轻，并且加上饮食控制，成为超重和肥胖患者长期体重维持成功的关键因素。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。尽管运动有这些已证实的效果，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。下丘脑在维持能量平衡中起着核心作用。为了确定下丘脑的因素，介导运动引起的食物摄入量和体重的变化，我们已经研究了下丘脑基因表达响应转轮活动使用微阵列分析。这些分析表明，甲状腺素运载蛋白（TTR）基因的表达诱导背内侧下丘脑（DMH）的运动大鼠。我们还表明，TTR的中枢注射抑制食物摄入。基于这些数据和先前的观察，TTR敲除导致增加的神经肽Y水平在小鼠外周和中枢神经系统中，我们假设，大脑TTR可能是一个主要的贡献因素，运动对食物摄入和能量平衡的影响，并与其他肽，在能量稳态中发挥重要作用。我们提出了两个具体的目标来检验这一假设。具体目标1将使用神经化学、药理学、遗传学和蛋白质水平的多种方法来确定脑TTR在控制能量平衡中的作用。具体目标2将通过基因表达测定和蛋白质组学分析来确定脑TTR在控制能量平衡中的靶位点和作用机制。总的来说，这项提案的发现不仅将促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。 公共卫生相关性：该拟议项目旨在确定运动对能量平衡影响的神经机制。这种鉴定将为预防和治疗肥胖提供潜在的靶点。

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.