Neuronal Inputs of Body Fat Regulation

描述（由申请人提供）：个体的遗传组成仍然是肥胖的主要诱发因素，最近的饮食和行为趋势也导致了目前的肥胖流行病。遗传背景是人类体重变异的一半原因，但我们目前只了解受遗传风险因素影响的几种途径。重要的是，我们对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，中枢神经系统在维持机体能量平衡方面显然起着重要但知之甚少的作用。这项建议的实验将针对果蝇体内脂肪调节中的神经元作用。果蝇是一个强大的肥胖模型：果蝇具有与哺乳动物相媲美的复杂生理学，加上流线型的基因组，其中单个基因通常具有多个冗余哺乳动物基因的功能。该项目的目标是通过识别大脑中需要其功能以防止过量体脂的区域来生成体脂调节的神经元地图，并确定在脂肪突变体的无偏筛选中确定的两个基因的功能，这两个基因似乎在大脑中起作用。其中一个新的脂肪基因是一种与脂联素结合的受体，脂联素是一种由脂肪细胞分泌的哺乳动物蛋白质，控制食物消耗和脂肪储存。识别苍蝇受体结合的分子可能揭示大脑与其他组织沟通以防止肥胖的新途径。另一个基因涉及与学习相关的行为，如成瘾，最重要的是，调节运动活动以应对营养供应。因此，这一因素可能代表了一个难以捉摸的机会来剖析身体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，并确定其治疗的新的潜在靶点。 公共卫生相关性：中枢神经系统-特别是大脑-似乎在生物体能量稳态中起着关键作用，但所涉及的途径却缺乏特征。这项工作将精确定位果蝇大脑中防止体内脂肪过多所需的区域，并揭示大脑为此目的协调其他组织功能的新途径，为新的人类肥胖治疗方法产生目标。

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.