Systemic regulation of energy homeostasis using a Drosophila Leptin model

使用果蝇瘦素模型对能量稳态的系统调节

• 批准号: 9267709
• 负责人: Akhila Rajan
• 金额: $ 24.9万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267709
• 关键词: Address; Adult; Affect; Affinity Chromatography; American; Anorexia; Binding; Biological Assay; Biology; Brain; Burn injury; Cardiovascular Diseases; Cells; Cereals; Chronic; Chronic Disease; Complex; Data Set; Desire for food; Diabetes Mellitus; Diet; Diet Modification; Disease; Drosophila genus; Eating; Energy Metabolism; Fat Body; Fatty acid glycerol esters; Food; Future Generations; Genes; Goals; Guidelines; Health; High Fat Diet; Homeostasis; Human; Hypothalamic structure; Imagery; Insulin; Intake; Knowledge; Lead; Leptin; Ligands; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mining; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neurons; Nutrient; Obesity; Organism; Pathway interactions; Physiology; Policies; Population; Process; Protein Secretion; Proteins; RNA; Regulation; Ribosomal Proteins; Ribosomes; Role; Route; Seminal; Signal Transduction; Sorting - Cell Movement; Stimulus; System; Techniques; Testing; Translating; Translations; Work; base; cell type; cytokine; energy balance; feeding; fly; gamma-Aminobutyric Acid; in vivo; innovation; insight; insulin secretion; lipid metabolism; neural circuit; neuronal circuitry; response; sugar

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.

描述（由申请人提供）：食物摄入和营养储存利用的协调被称为“能量稳态”。当这一基本过程被破坏时，可能会导致许多疾病，特别是肥胖、厌食和糖尿病。我发现果蝇中 JAK/STAT 通路的配体称为 Unpaired2 (Upd2)，其功能类似于果蝇中的瘦素。它向大脑中的 GABA 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 信号传导通过缓解 GABA 神经元对胰岛素生成细胞 (IPC) 的抑制音来促进胰岛素分泌。该电路模块与瘦素用于控制哺乳动物系统能量平衡的电路模块惊人地相似。在本提案中，我建议使用果蝇系统瘦素模型研究以下内容：i）脂肪水平如何在分泌水平上调节Upd2； ii) 确定瘦素和 Upd2 信号传导影响 GABA 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作用还是转录后作用。然后，我将确定 STAT 的靶标和/或其蛋白质相互作用因子，它们参与 Upd2 介导的 GABA 神经元调节； iii）最后，我计划使用一种创新技术来识别对特定类型饮食做出反应的神经元，并确定此类神经元组的分子特征。预计这将提供有关对饮食变化做出反应的神经元群的细胞识别的信息。这将指导后续研究一组特定的神经元如何影响系统能量代谢以响应特定的饮食。总体而言，拟议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) 这些分子利用什么分子机制来改变神经元生理学以响应饮食变化。美国农业部发布的 2010 年政策文件《美国人膳食指南》发现，增加脂肪、糖和精制谷物的摄入量来代替富含蛋白质的食物，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，并且重要的是将为复杂代谢紊乱​​的治疗提供相关见解。