Invertebrate Models of Fat Storage

描述(申请人提供)：肥胖和糖尿病的相互交织的流行已经产生了一种公共健康危机，需要对脂肪生物学和新陈代谢有更好的了解。通过线虫和黑腹线虫的遗传筛选，我们发现了许多无脊椎动物脂肪储存/代谢的遗传调节因子，它们在哺乳动物中也具有保守的作用。我们将注意力集中在脂肪(ADP)基因上，因为它在蠕虫、苍蝇和哺乳动物中具有显著的抗肥胖和抗糖尿病功能，突显了它在新陈代谢中的重要性和作为治疗靶点的潜力。这项提议的目标是解开这些惊人效应背后的生理和分子机制。我们希望这些代谢和分子研究将加强我们对哺乳动物新陈代谢的了解，并导致肥胖和糖尿病的新治疗策略。ADP调节着一条古老的代谢途径。降低蠕虫、果蝇、哺乳动物脂肪细胞和小鼠的ADP功能会刺激脂肪形成(肥胖)，ADP突变的果蝇和小鼠患有糖尿病。这些效应是由于ADP在脂肪细胞内的作用，因为脂肪细胞限制显性负值ADP的表达会导致肥胖和糖尿病。相反，脂肪选择性表达野生型ADP会产生瘦小、对葡萄糖敏感的果蝇和小鼠。然而，关于体内代谢表型，仍有几个未被探索的问题。在目标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，在这些模型中，ADP的作用被修改。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)。同时(目标III)，我们揭开了ADP效应背后的分子机制。我们的初步研究表明，ADP与几个ADP相互作用蛋白(AIP)结合并发挥作用，AIP调节染色质动态和基因转录。ADP如何调节这些AIP的统一机制源于我们的数据，即ADP似乎控制着一种新的泛素E3连接酶复合体的底物特异性。在AIM III中，我们将描述E3连接酶在脂肪生物学中的作用；这一知识对于开发最终操纵ADP途径以达到治疗目的所需的基本见解至关重要。 与公共健康相关：调节脂肪储存和新陈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ADP具有显著的生物学、分子和生化性质，预示着治疗的潜力和新的机制，因此我们将注意力集中在一种在蠕虫、苍蝇和哺乳动物中具有抗肥胖和抗糖尿病功能的脂肪(ADP)上。我们的目标是揭开保守这些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。

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.