Role of SMRT and NCoR in adipocyte differentation and function

描述(申请人提供)：肥胖是胰岛素抵抗的主要原因，肥胖率上升是2型糖尿病发病率增加的原因。脂肪细胞除了作为甘油三酯具有吸收和储存能量的功能外，还是一种复杂的内分泌细胞，调节摄食行为和胰岛素的作用。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了脂肪质量，但改善了胰岛素敏感性。确定调节脂肪细胞功能的因素对于了解脂肪细胞如何调节这些不同的过程是至关重要的。我们以前已经证明，在3T3-L1脂肪形成过程中，两种核受体辅阻遏物--维甲酸和甲状腺激素受体沉默介体(SMRT)和核受体辅阻遏物(NCoR)--抑制脂肪细胞的基因表达。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决定分化的脂肪细胞功能的假设。在目标2中，我们将建立SMRT缺陷的小鼠胚胎成纤维细胞，以验证辅抑制子调控原代细胞脂肪生成和脂肪细胞凋亡的假说。在目标3中，我们将确定SMRT在体内对脂肪细胞功能和胰岛素敏感性的作用。通过结合对脂肪细胞系、小鼠胚胎成纤维细胞和分离的脂肪细胞的体外分析，以及通过建立新的辅阻遏物缺乏的小鼠模型来在体内验证我们的假设，我们将剖析脂肪细胞辅阻遏物作用的分子机制。如果我们要设计治疗肥胖和糖尿病的新方法，了解SMRT和NCoR在脂肪细胞生物学中的作用是至关重要的。公共卫生相关性：肥胖是2型糖尿病发展的危险因素，糖尿病是导致失明、肾脏疾病、截肢和死亡的主要原因。这些研究的目的是验证SMRT和NCoR这两种蛋白质对脂肪细胞(脂肪细胞)功能和身体对胰岛素的反应能力至关重要的假设。这些结果将有助于设计治疗糖尿病患者的新药。

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