Invertebrate Models of Fat Storage

无脊椎动物脂肪储存模型

基本信息

批准号：
7785513
负责人：
JONATHAN M GRAFF
金额：
$ 44.65万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7785513
关键词：
Address Adipocytes Adipose tissue Attention Binding Biochemical Biological Biological Assay Biology Brown Fat Caenorhabditis elegans Cell Nucleus Cells Chromatin Complex Consumption Data Diabetes Mellitus Diet Dominant-Negative Mutation Employee Strikes Energy Metabolism Epidemic Fatty acid glycerol esters Gene Expression Genes Genetic Genetic Polymorphism Genetic Screening Genetic Transcription Glucose Goals HDAC3 gene Healthcare Histones Human Intake Invertebrates Knowledge Lead Link Liver Mammalian Cell Mammals Mediator of activation protein Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Mutant Strains Mice Obesity Pathway interactions Phenotype Physiological Physiology Play Process Property Proteins Public Health Regulation Role Specificity Stimulus Structure Substrate Specificity Testing Therapeutic Tissues Transcriptional Regulation Transgenic Organisms Ubiquitination Weight adipocyte biology blood glucose regulation feeding fly improved in vivo insight mouse model mutant new therapeutic target novel novel therapeutics public health relevance receptor response selective expression stem therapeutic target ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The intertwined epidemics of obesity and diabetes have produced a public health crisis that demands an improved understanding of fat biology and metabolism. Through genetic screens in C. elegans and D. melanogaster, we identified many genetic regulators of invertebrate fat storage/metabolism that also have a conserved role in mammals. We focused our attention on one gene, Adipose (Adp), because its striking anti-obesity and anti-diabetes function in worms, flies, and mammals highlight its importance in metabolism and potential as a therapeutic target. The goal of this proposal is to unravel the physiological and molecular mechanisms underlying these striking effects. Our hope is that these metabolic and molecular studies will enhance our understanding of mammalian metabolism and lead to novel therapeutic strategies for obesity and diabetes. Adp regulates an ancient metabolic pathway. Reducing Adp function in worms, flies, mammalian adipogenic cells, and mice stimulates fat formation (obesity) and Adp mutant flies and mice have diabetes. These effects result from actions of Adp within adipocytes, as adipocyte-restricted expression of dominant negative Adp in mice caused obesity and diabetes. Conversely, fat selective expression of wild-type Adp produces lean, glucose sensitive flies and mice. Yet, there remain several unexplored issues relating to the in vivo metabolic phenotypes. In Aim I, we will characterize the metabolic physiology of our various invertebrate and mouse models in which Adp action is modified. These studies will rigorously test our hypothesis that altered energy expenditure underlies the anti-obesity actions of Adp. Then, we will examine how Adp regulates the responses to high fat diet and other metabolically relevant stimuli (Aims I and II). In parallel (Aim III), we unravel the molecular mechanisms underlying the Adp effects. Our initial studies show that Adp binds to and functions with several Adp interacting proteins (AIPs) that regulate chromatin dynamics and gene transcription. A unifying mechanism for how Adp regulates these AIPs stems from our data that Adp appears to control the substrate specificity of a novel ubiquitin E3 ligase complex. In Aim III, we will characterize the role that this E3 ligase has in fat biology; knowledge that is key in order to develop the fundamental insights required to ultimately manipulate the Adp pathway for therapeutic ends. PUBLIC HEALTH RELEVANCE: The ability to regulate fat storage and metabolism are fundamental processes. However, the dual epidemics of obesity and diabetes endanger millions and are altering our health care landscape. This crisis that could be addressed by identifying genes that influence fat biology and metabolism. Because of striking biological, molecular, and biochemical properties, indicating therapeutic potential and novel mechanisms, we focused our attention on one, Adipose (Adp), that has anti-obesity and anti-diabetes functions in worms, flies, and mammals. Our goal is to unravel the physiological and molecular mechanisms underlying conserved these effects, which we believe will enhance our understanding of adipocyte biology and may lead to novel therapeutic targets for obesity and diabetes.

描述（由申请人提供）：肥胖和糖尿病的相互交织的流行病已经引起了公共卫生危机，要求对脂肪生物学和代谢有进一步的了解。通过秀丽隐杆线虫和梅拉诺氏菌中的遗传筛选，我们确定了许多无脊椎动物脂肪储存/代谢的遗传调节剂，这些调节剂在哺乳动物中也具有保守作用。我们将注意力集中在一个基因，脂肪（ADP）上，因为它引人注目的抗肥胖和抗糖尿病在蠕虫，苍蝇和哺乳动物中的作用突出了其在代谢中的重要性，并作为治疗靶标的潜力。该建议的目的是揭示这些引人注目的作用的生理和分子机制。我们的希望是，这些代谢和分子研究将增强我们对哺乳动物代谢的理解，并为肥胖和糖尿病带来新的治疗策略。 ADP调节古老的代谢途径。降低蠕虫，果蝇，哺乳动物脂肪生成细胞的ADP功能，而小鼠刺激脂肪形成（肥胖），而ADP突变蝇和小鼠患有糖尿病。这些作用是由ADP在脂肪细胞中的作用引起的，因为小鼠中主要阴性ADP的脂肪细胞限制性表达会导致肥胖和糖尿病。相反，野生型ADP的脂肪选择性表达会产生瘦葡萄糖敏感的果蝇和小鼠。然而，与体内代谢表型有关的问题仍然存在几个未开发的问题。在AIM I中，我们将描述各种无脊椎动物和小鼠模型的代谢生理，其中ADP动作被修改。这些研究将严格检验我们的假设，即改变能量消耗是ADP抗肥胖作用的基础。然后，我们将研究ADP如何调节对高脂肪饮食和其他代谢相关刺激的反应（目标I和II）。在并行（AIM III）中，我们揭示了ADP效应的分子机制。我们的初步研究表明，ADP与调节染色质动力学和基因转录的几种ADP相互作用蛋白（AIP）结合并功能。 ADP如何调节这些AIP的一种统一机制源于我们的数据，ADP似乎控制了新型泛素E3连接酶复合物的底物特异性。在AIM III中，我们将表征E3连接酶在脂肪生物学中的作用。为了开发最终操纵治疗目的的ADP途径所需的基本见解，这是关键的知识。公共卫生相关性：调节脂肪存储和代谢的能力是基本过程。但是，肥胖和糖尿病的双重流行病危害了数百万，并且正在改变我们的医疗保健局势。这场危机可以通过识别影响脂肪生物学和代谢的基因来解决。由于表明治疗潜力和新型机制的生物学，分子和生化特性引人注目，我们将注意力集中在一种，脂肪（ADP）上，脂肪（ADP）具有抗肥胖和抗糖尿病，在蠕虫，蝇和哺乳动物中起作用。我们的目标是阐明这些作用的生理和分子机制，我们认为这将增强我们对脂肪细胞生物学的理解，并可能导致肥胖和糖尿病的新型治疗靶标。