Invertebrate Models of Fat Storage

无脊椎动物脂肪储存模型

• 批准号: 8068076
• 负责人: JONATHAN M GRAFF
• 金额: $ 10万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2010-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068076
• 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

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产生了公共卫生危机，需要对脂肪生物学和代谢有更好的了解。通过遗传筛选，在C. elegans和D.通过对黑腹鱼的研究，我们鉴定了许多在哺乳动物中也具有保守作用的无脊椎动物脂肪储存/代谢的遗传调节因子。我们将注意力集中在一个基因上，Adipose（ADP），因为它在蠕虫，苍蝇和哺乳动物中的抗肥胖和抗糖尿病功能突出了它在代谢中的重要性和作为治疗靶点的潜力。这项提案的目标是解开这些惊人效果背后的生理和分子机制。我们希望这些代谢和分子研究将增强我们对哺乳动物代谢的理解，并导致肥胖和糖尿病的新治疗策略。Adp调节一种古老的代谢途径。降低蠕虫、苍蝇、哺乳动物脂肪形成细胞和小鼠中的ADP功能会刺激脂肪形成（肥胖），而ADP突变的苍蝇和小鼠会患糖尿病。这些作用是由于ADP在脂肪细胞内的作用，因为在小鼠中脂肪细胞限制显性负性ADP的表达导致肥胖和糖尿病。相反，野生型ADP的脂肪选择性表达产生瘦的、葡萄糖敏感的苍蝇和小鼠。然而，仍然存在与体内代谢表型相关的几个未探索的问题。在目的I中，我们将描述我们的各种无脊椎动物和小鼠模型的代谢生理学特征，其中ADP作用被修改。这些研究将严格验证我们的假设，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如何调节对高脂饮食和其他代谢相关刺激的反应（目的I和II）。在平行（目的III），我们解开ADP效应的分子机制。我们的初步研究表明，ADP结合和功能与几个ADP相互作用蛋白（AIP），调节染色质动力学和基因转录。ADP如何调节这些AIP的统一机制源于我们的数据，即ADP似乎控制一种新型泛素E3连接酶复合物的底物特异性。在目标III中，我们将描述这种E3连接酶在脂肪生物学中的作用;为了开发最终操纵ADP途径用于治疗目的所需的基本见解，知识是关键。 公共卫生相关性：调节脂肪储存和代谢的能力是基本过程。然而，肥胖和糖尿病的双重流行危及数百万人，并正在改变我们的医疗保健格局。这一危机可以通过识别影响脂肪生物学和新陈代谢的基因来解决。由于具有显著的生物学、分子和生化特性，显示出治疗潜力和新的机制，我们将注意力集中在一种脂肪（Adp）上，它在蠕虫、苍蝇和哺乳动物中具有抗肥胖和抗糖尿病功能。我们的目标是揭示这些保守效应背后的生理和分子机制，我们相信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治疗靶点。