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，它可能导致许多疾病，特别是肥胖症，厌食症和糖尿病。我发现果蝇JAK/STAT途径的配体，称为Unpaired 2（Upd 2），功能类似于果蝇中的瘦素。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（IPC）的抑制性张力来促进胰岛素分泌。这个电路模块令人联想到瘦素用于控制哺乳动物系统中的能量平衡。在这个提议中，使用果蝇系统Leptin模型，我建议研究以下内容：i）脂肪水平如何在分泌水平上调节Upd 2; ii）确定Leptin和Upd 2信号传导影响GABA能神经元放电的机制是未知的。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/或它的蛋白质相互作用，参与更新2介导的GABA神经元的调节; iii）最后，使用一种创新的技术，我计划确定神经元响应特定种类的饮食，并确定这样的神经元组的分子概况。这有望提供有关对饮食变化作出反应的神经元组的细胞识别的信息。这将指导随后的研究，即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调节脂肪抑制分子以响应营养储存的变化; ii）这些分子部署了什么样的分子机制来改变神经元生理学以响应饮食变化。2010年美国农业部发布的政策文件《美国人膳食指南》发现，增加脂肪、糖和精制谷物的摄入量，而不是富含蛋白质的食物，是心血管疾病、糖尿病和某些形式的癌症等慢性疾病的主要原因。为了否定高脂高糖饮食的影响，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，我将为复杂的代谢紊乱的治疗提供相关的见解。