Systemic regulation of energy homeostasis using a Drosophila Leptin model

描述（由申请人提供）：食物摄入和营养储备利用的协调被称为“能量稳态”。当这个基本过程被破坏时，它会导致许多疾病，特别是肥胖、厌食症和糖尿病。我发现在果蝇中有一种JAK/STAT通路的配体，名为Unpaired2 (Upd2)，其功能与果蝇中的瘦素类似。它向大脑中的gaba能神经元发出生物体脂肪状态的信号。目前的工作模型表明，JAK/STAT信号通过减轻GABA神经元对胰岛素产生细胞（IPCs）的抑制张力来促进胰岛素分泌。这个电路模块与哺乳动物系统中瘦素用来控制能量平衡的电路模块惊人地相似。在本提案中，使用果蝇系统瘦素模型，我建议研究以下内容：I)脂肪水平如何在分泌水平调节Upd2；ii)确定瘦素和Upd2信号影响gaba能神经元放电的机制尚不清楚。我将测试STAT在gaba能神经元中的作用是转录的还是转录后的。然后，我将确定STAT的目标和/或其蛋白质相互作用物，这些相互作用物参与Upd2介导的GABA神经元的调节；iii)最后，使用一种创新技术，我计划识别对特定种类饮食有反应的神经元，并确定这些神经元群的分子特征。这有望提供对饮食变化作出反应的神经元组的细胞识别信息。这将指导后续的研究，即一组特定的神经元如何影响对特定饮食的全身能量代谢。总的来说，提出的目标将解决瘦素生物学中的两个关键问题：i)如何在翻译和分泌水平上调节脂肪分子以响应营养储存的变化；Ii)这些分子是通过什么分子机制来改变神经元生理以应对饮食变化的。美国农业部2010年发布的政策文件《美国人膳食指南》发现，脂肪、糖和精制谷物的摄入量增加，而不是富含蛋白质的食物，是导致心血管疾病、糖尿病和某些癌症等慢性疾病的主要原因。为了消除高脂肪和高糖饮食的影响，阐明全身脂肪代谢的分子基础至关重要。我在这里提出的研究有可能阐明为什么我们更喜欢富含脂肪的食物而不是富含蛋白质的饮食，重要的是将为复杂代谢紊乱的治疗提供相关的见解。

DESCRIPTION (provided by applicant): Coordination of food intake and utilization of nutrient stores is referred to as "energy homeostasis". When this fundamental process is disrupted, it can lead to a number of disorders, in particular, obesity, anorexia and diabetes. I found that a ligand of the JAK/STAT pathway in flies, called Unpaired2 (Upd2), functions like Leptin in fruit flies. It signals the organism's fat status to GABAergic neurons in the brain. Current working model suggests that JAK/STAT signaling promotes insulin secretion by relieving the inhibitory tone of GABA neurons on insulin producing cells (IPCs). This circuit module is strikingly reminiscent to that used by Leptin to control energy balance in the mammalian system. In this proposal, using the Drosophila system Leptin model, I propose to investigate the following: i) how fat levels regulate Upd2 at the level of secretion; ii) identify mechanism(s) by which Leptin and Upd2 signaling affects GABAergic neuronal firing are unknown. I will test whether the role for STAT in GABAergic neurons is transcriptional or post- transcriptional. Then, I will identify STAT's targets and/or its protein interactors which are involved in Upd2- mediated regulation of GABA neurons; iii) finally, using an innovative technique, I plan to identify neurons which respond to particular sorts of diets and determine the molecular profile of such neuronal groups. This is expected to provide information about the cellular identify of the neuronal group which responds to dietary changes. This will guide subsequent studies of how a particular set of neurons influence systemic energy metabolism in response to specific diets. Overall, the proposed aims will address two key issues in Leptin Biology: i) how adipostatic molecules are regulated at the level of translation and secretion in response to changes in nutrient stores; ii) what molecular mechanisms are deployed by these molecules to alter neuronal physiology in response to dietary changes. The 2010 policy document-Dietary guidelines for Americans- issued by the USDA finds that, an increased intake of fats, sugars and refined grains in lieu of protein-rich food, is a primary cause of chronic diseases such as cardiovascular disorders, diabetes and some forms cancer. In order to negate the effects of high fat and sugar diets, elucidating the molecular basis of systemic fat metabolism is crucial. The studies I propose here have the potential to illuminate why we prefer fat-rich foods to a protein-rich diet and importantl will provide relevant insights for the treatment of complex metabolic disorders.