Regulation of Insulin Sensitivity by the Ubiquitin Ligase Siah2

描述(申请人提供)：肥胖是一个主要的公共卫生问题，因为肥胖相关的慢性疾病，如2型糖尿病的增加。肥胖相关的胰岛素抵抗和2型糖尿病的发展可能与脂肪组织以甘油三酯形式充分储存能量的能力失调有关，导致非脂肪组织中的体外脂质堆积。核激素受体过氧化物酶体增殖激活受体γ(PPAR？)在脂肪细胞中是将脂肪代谢与葡萄糖动态平衡和胰岛素敏感性相结合的关键因素。激活PPAR？通过噻唑烷二酮(TZD)类抗糖尿病药物与脂肪组织的扩张和增强脂肪组织储存膳食脂肪的能力有关。这些药物会改变PPAR吗？活动和PPAR？蛋白质水平，这表明了解PPAR之间的联系？活动和PPAR？蛋白质稳定性可能会为肥胖如何导致NIDDM提供新的见解。PPAR？脂肪细胞的稳定性是由泛素蛋白酶体途径的酶调节的，泛素蛋白酶体途径是一种高度选择性的信号通路，通过用多个泛素多肽标记蛋白质来将蛋白质靶向蛋白酶体。通过基于siRNA的筛选，我们鉴定了一个调节PPAR？的泛素连接酶Siah2。蛋白质水平和PPAR？脂肪细胞的活性。我们使用Siah2KO小鼠模型的初步研究表明，Siah2调节PPAR？消除Siah2可以预防肥胖相关的胰岛素抵抗。我们假设Siah2依赖于PPAR的调节？运动将肥胖与脂肪组织炎症和胰岛素抵抗联系在一起。我们的目标是提供对Siah2在控制PPAR？脂肪组织中的蛋白质水平、胰岛素敏感性和炎症。在具体目标1中，我们将测试 假设依赖Siah2的PPAR？限制PPAR？通过增加PPAR？的配体依赖的蛋白酶体降解来增强活性。具体目标2将评估Siah2对脂肪组织炎症的影响。在特定的目标3中，我们将检验脂肪细胞中的Siah2通过调节PPAR？调节全身胰岛素敏感性的假设。脂肪和非脂肪组织之间的活性和脂肪分配。综上所述，这些研究将为PPAR？这项研究将揭示脂肪组织在调节胰岛素敏感性中的活性和作用，并将推动我们的目标，即确定泛素-蛋白酶体系统是否代表了肥胖相关胰岛素抵抗和2型糖尿病治疗的新靶点。

DESCRIPTION (provided by applicant): Obesity is a major public health problem due to the increase in obesity-related chronic diseases such as type 2 diabetes. The development of obesity-related insulin resistance and type 2 diabetes can be linked to dysregulation of the ability of adipose tissue to adequately store energy in the form of triglycerides, leading to ectopc lipid accumulation in non-adipose tissues. The nuclear hormone receptor peroxisome proliferation-activated receptor gamma (PPAR?) in adipocytes is a key factor in integrating lipid metabolism with glucose homeostasis and insulin sensitivity. Activation of PPAR? by the thiazolidinedione (TZD) class of anti-diabetic drugs is associated with expansion of the adipose tissue and enhanced ability of the adipose tissue to store dietary lipids. These drugs alter PPAR? activity and PPAR? protein levels, an indication that understanding the link between PPAR? activity and PPAR? protein stability may offer new insights into how obesity contributes to NIDDM. PPAR? stability in adipocytes is regulated by enzymes of the ubiquitin proteasome pathway, a highly selective signaling pathway that targets proteins to the proteasome by tagging the protein with multiple ubiquitin polypeptides. Using siRNA-based screening, we identified a ubiquitin ligase, Siah2 that regulates PPAR? protein levels and PPAR? activity in adipocytes. Our preliminary studies using a Siah2KO mouse model show Siah2 regulates PPAR? protein levels and inflammation in adipose tissue and that eliminating Siah2 prevents obesity-related insulin resistance. We hypothesize that Siah2-dependent regulation of PPAR? activity links obesity with adipose tissue inflammation and insulin resistance. Our goal is to provide mechanistic insight into the role of Siah2 in controlling the relationship between PPAR? protein levels, insulin sensitivity and inflammation in adipose tissue. In Specific Aim 1, we will test the hypothesis that Siah2-dependent modification of PPAR? limits PPAR? activity by increasing ligand-dependent proteasomal degradation of PPAR?. Specific aim 2 will assess the effect of Siah2 on adipose tissue inflammation. In specific aim 3, we will test the hypothesis that Siah2 in adipocytes regulates systemic insulin sensitivity via regulation of PPAR? activity and lipid partitioning between adipose and non-adipose tissue. Together, these studies will provide new insight into the relationship between PPAR? activity and the role of adipose tissue in regulating insulin sensitivity and will advance our goal of determining if the ubiquitin-proteasome system represents a novel therapeutic target in the treatment of obesity-related insulin resistance and type 2 diabetes.