Neuronal Inputs of Body Fat Regulation

个人描述(申请人提供)：个人的基因构成仍然是肥胖的主要易感因素，最近的饮食和行为趋势也是目前肥胖流行的原因之一。遗传背景是人类群体体重变化的大约一半原因，但我们目前只了解到受遗传风险因素影响的少数途径。重要的是，我们掌握的关于肥胖易感基因的有限信息表明，许多基因主要在大脑中表达。事实上，中枢神经系统显然在维持机体能量平衡方面扮演着重要的角色，但人们对此知之甚少。这项提议中的实验将针对果蝇黑腹果蝇体内脂肪调节中的神经元角色。果蝇是一个强大的肥胖模型：果蝇拥有与哺乳动物相媲美的复杂生理，以及精简的基因组，在基因组中，单个基因往往起到多个多余哺乳动物基因的作用。该项目的目标是通过识别大脑中防止过量身体脂肪所需的功能区域来生成身体脂肪调节的神经元图谱，并确定在脂肪突变的无偏见筛查中确定的两个基因的功能，这两个基因似乎在大脑中发挥作用。其中一个新的脂肪基因是一个未知的受体，与那些与脂联素结合的受体有关，脂联素是一种由脂肪细胞分泌的哺乳动物蛋白质，控制着食物的消耗和脂肪的储存。识别苍蝇受体结合的分子可能会揭示大脑与其他组织沟通以防止肥胖的新途径。另一个基因与成瘾等与学习相关的行为有关，最重要的是，与调节运动活动对营养供应的反应有关。因此，这个因素可能代表着一个原本难以捉摸的机会来剖析体力活动和能量储存之间的关系。这些研究将为人类肥胖的神经元成分提供新的见解，并为其治疗确定新的潜在靶点。 与公共健康相关：中枢神经系统--尤其是大脑--似乎在生物体能量动态平衡中起着关键作用，但涉及的通路特征不佳。这项工作将精确定位果蝇大脑中防止体内过量脂肪所需的区域，并发现大脑为此目的协调其他组织功能的新途径，为人类肥胖治疗产生新的靶点。

DESCRIPTION (provided by applicant): An individual's genetic makeup remains a major predisposing factor to obesity, with recent trends in diet and behavior also contributing to the current obesity epidemic. Genetic background is responsible for about half of the variation in body weight within human populations, but we currently understand only a few of the pathways affected by hereditary risk factors. Importantly, the limited information we have about obesity-predisposing genes suggests that many are expressed primarily in the brain. Indeed, the central nervous system clearly plays important but poorly understood roles in maintaining organismal energy homeostasis. Experiments in this proposal will target neuronal roles in body fat regulation in the fruit fly Drosophila melanogaster. Drosophila is a powerful obesity model: flies have a complex physiology rivaling that of mammals, plus a streamlined genome in which a single gene often serves the function of multiple redundant mammalian genes. The goals of this project are to generate a neuronal map of body fat regulation by identifying regions of the brain whose functions are required to prevent excess body fat, and to determine the functions of two genes that were identified in an unbiased screen for fat mutants and which appear to operate in the brain. One of the new fat genes is an uncharacterized receptor related to those that bind adiponectin, a mammalian protein secreted from fat cells that controls food consumption and fat storage. Identifying the molecule bound by the fly receptor may reveal a new pathway by which the brain communicates with other tissues to prevent obesity. The other gene has been implicated in both learning-related behaviors like addiction and, most importantly, the regulation of locomotor activity in response to nutrient availability. Thus, this factor may represent an otherwise elusive opportunity to dissect the relationship between physical activity and energy storage. These studies will provide new insights into the neuronal components of human obesity, and identify new potential targets for its treatment. PUBLIC HEALTH RELEVANCE: The central nervous system - in particular, the brain - appears to play critical roles in organismal energy homeostasis, but the pathways involved are poorly characterized. This work will pinpoint regions of the Drosophila brain required to prevent excess body fat, and uncover new pathways by which the brain coordinates the functions of other tissues for this purpose, generating targets for new human obesity treatments.