Role of SMRT and NCoR in adipocyte differentiation and function

肥胖是胰岛素抵抗的主要原因，肥胖率的上升是导致胰岛素抵抗增加的原因。 2型糖尿病的发病率。除了在吸收和储存能量方面的功能外， 脂肪细胞是一种复杂的内分泌细胞，调节进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，噻唑烷二酮类药物 增加脂肪量，但改善胰岛素敏感性。确定调节脂肪细胞功能的因素是至关重要的 来了解脂肪细胞如何调节这些不同的过程。我们之前已经证明，两个 核受体辅阻遏物，类维生素A和甲状腺激素受体（SMRT）的沉默介质， 核受体辅阻遏物（NCoR）在脂肪形成过程中抑制脂肪细胞基因表达。在 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决定分化脂肪细胞的功能。在目标2中，我们将开发小鼠胚胎 SMRT和/或NCoR缺陷的成纤维细胞，以检验辅阻遏物调节脂肪形成的假设 和脂肪细胞在原代细胞中的存活。在目的3中，我们将定义SMRT和NCoR在脂肪细胞中的作用， 功能和胰岛素敏感性。通过结合脂肪细胞系的体外分析，小鼠 胚胎成纤维细胞和分离的脂肪细胞，并通过开发新的小鼠模型的辅阻遏物， 为了在体内验证我们的假设，我们将剖析SMRT的分子机制， 脂肪细胞中的NCoR作用。了解辅阻遏物在脂肪细胞生物学中的作用至关重要，如果我们 是设计治疗肥胖和糖尿病的新方法。 相关性：肥胖是2型糖尿病的危险因素，糖尿病是2型糖尿病的主要危险因素。 导致失明、肾病、截肢和死亡。这些研究的目的是测试 假设两种蛋白质，SMRT和NCoR，在脂肪细胞（脂肪细胞）的功能和能力中是重要的， 身体对胰岛素产生反应。这些结果将有助于设计新的药物来治疗患者 患有糖尿病

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 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 and/or NCoR to test the hypothesis that corepressors regulate adipogenesis and adipocyte survival in primary cells. In Aim 3, we will define the roles of SMRT and NCoR 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 SMRT and NCoR action in the adipocyte. Understanding the roles of corepressors in adipocyte biology is crucial if we are to design novel approaches to the treatment of obesity and diabetes. 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.