Role of SMRT and NCoR in adipocyte differentation and function

描述（由申请人提供）：肥胖是胰岛素抵抗的主要原因，肥胖率的上升是2型糖尿病患病率上升的原因。脂肪细胞除了具有摄取和储存甘油三酯等能量的功能外，还是一种复杂的内分泌细胞，调节摄食行为和胰岛素作用。然而，肥胖和糖尿病之间的关系是复杂的;例如，噻唑烷二酮类增加脂肪量，但改善胰岛素敏感性。定义调节脂肪细胞功能的因素以了解脂肪细胞如何调节这些不同的过程是至关重要的。我们以前已经表明，两个核受体辅阻遏物，类维生素A和甲状腺激素受体（SMRT）和核受体辅阻遏物（NCoR）的沉默介质，抑制脂肪细胞基因表达在3 T3-L1脂肪形成。在拟议的研究中，我们将测试新的假设来解释SMRT和NCoR如何调节脂肪细胞分化，脂肪细胞功能和胰岛素敏感性。在目标1中，我们将检验SMRT和NCoR决定分化脂肪细胞功能的假设。在目标2中，我们将开发SMRT缺陷的小鼠胚胎成纤维细胞，以检验辅阻遏物调节原代细胞中脂肪形成和脂肪细胞凋亡的假设。在目标3中，我们将定义SMRT在体内脂肪细胞功能和胰岛素敏感性中的作用。通过结合脂肪细胞系，小鼠胚胎成纤维细胞，和分离的脂肪细胞的体外分析，并通过开发新的小鼠模型的辅阻遏蛋白缺乏症，以测试我们的假设在体内，我们将解剖辅阻遏蛋白在脂肪细胞中的作用的分子机制。了解SMRT和NCoR在脂肪细胞生物学中的作用是至关重要的，如果我们要设计新的方法来治疗肥胖症和糖尿病。公共卫生相关性：肥胖是2型糖尿病发展的危险因素，糖尿病是失明、肾病、截肢和死亡的主要原因。这些研究的目的是检验两种蛋白质SMRT和NCoR在脂肪细胞（脂肪细胞）功能和身体对胰岛素反应的能力中很重要的假设。这些结果将有助于设计治疗糖尿病患者的新药物

DESCRIPTION (provided by applicant): Obesity is a major cause of insulin resistance and rising rates of obesity are responsible for the increasing prevalence of type 2 diabetes mellitus. In addition to its function in the uptake and storage of energy as triglyceride, the adipocyte is a complex endocrine cell that regulates feeding behavior and insulin action. However, the relationship between adiposity and diabetes is complex; for example, thiazolidinediones increase fat mass, yet improve insulin sensitivity. It is vital to define factors that regulate adipocyte function to understand how the adipocyte modulates such diverse processes. We have previously shown that two nuclear receptor corepressors, the silencing mediator of retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressor (NCoR), repress adipocyte gene expression during 3T3-L1 adipogenesis. In the proposed studies, we will test novel hypotheses to explain how SMRT and NCoR regulate adipocyte differentiation, adipocyte function, and insulin sensitivity. In Aim 1, we will test the hypothesis that SMRT and NCoR dictate the function of the differentiated adipocyte. In Aim 2, we will develop mouse embryonic fibroblasts deficient in SMRT to test the hypothesis that corepressors regulate adipogenesis and adipocyte apoptosis in primary cells. In Aim 3, we will define the roles of SMRT in adipocyte function and insulin sensitivity in vivo. By combining in vitro analysis of adipocyte cell lines, mouse embryonic fibroblasts, and isolated adipocytes, and by developing novel mouse models of corepressor deficiency to test our hypotheses in vivo, we will dissect the molecular mechanisms underlying corepressor action in the adipocyte. Understanding the roles of SMRT and NCoR in adipocyte biology is crucial if we are to design novel approaches to the treatment of obesity and diabetes. PUBLIC HEALTH RELEVANCE: Obesity is a risk factor for the development of type 2 diabetes mellitus, and diabetes is a major cause or blindness, kidney disease, amputation, and death. The goal of these studies is to test the hypothesis that two proteins, SMRT and NCoR, are important in fat cell (adipocyte) function and the ability of the body to respond to insulin. These results will be helpful in the design of new medications to treat patients with diabetes