Regulation of Insulin Sensitivity by the Ubiquitin Ligase Siah2

泛素连接酶 Siah2 对胰岛素敏感性的调节

• 批准号: 8695734
• 负责人: ZELPHA ELIZABETH FLOYD
• 金额: $ 29.6万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695734
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adipose tissue; Agreement; Animal Model; Antidiabetic Drugs; Chronic; Chronic Disease; DNA Binding; Data; Development; Diet; Dietary Fats; Disease; Drosophila genus; Enzymes; Gene Expression; Goals; Homologous Gene; Human; Hypertrophy; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intake; Learning; Ligands; Link; Lipids; Mediating; Metabolic syndrome; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Obesity; Pathway interactions; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Production; Proteins; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; System; Testing; Thiazolidinediones; Tissues; Triglycerides; Ubiquitin; adipocyte biology; base; blood glucose regulation; carbohydrate metabolism; cytokine; glucose metabolism; insight; insulin sensitivity; interest; lipid metabolism; macrophage; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutics; obesity treatment; polypeptide; prevent; public health relevance; receptor; response; screening; ubiquitin ligase

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.

描述（由申请人提供）：由于肥胖相关慢性疾病（如2型糖尿病）的增加，肥胖是一个主要的公共卫生问题。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异位脂质积累。核激素受体过氧化物酶体增殖激活受体γ（PPAR？）是整合脂质代谢与葡萄糖稳态和胰岛素敏感性的关键因素。激活PPAR？噻唑烷二酮（TZD）类抗糖尿病药物与脂肪组织的扩张和脂肪组织储存膳食脂质的能力增强有关。这些药物会改变PPAR吗？活动和PPAR？蛋白质水平，一个迹象表明，了解之间的联系，过氧化物酶体增殖物激活受体？活动和PPAR？蛋白质的稳定性可能为肥胖如何导致NIDDM提供新的见解。PPAR？脂肪细胞中的稳定性由泛素蛋白酶体途径的酶调节，该途径是一种高度选择性的信号传导途径，其通过用多个泛素多肽标记蛋白质而将蛋白质靶向蛋白酶体。使用siRNA为基础的筛选，我们确定了一个泛素连接酶，Siah 2调节过氧化物酶体增殖物激活受体？蛋白质水平和过氧化物酶体增殖物激活受体？在脂肪细胞中的活性。我们的初步研究使用Siah 2KO小鼠模型显示Siah 2调节PPAR？蛋白质水平和脂肪组织中的炎症，消除Siah 2可以预防肥胖相关的胰岛素抵抗。我们推测，Siah 2依赖的调节过氧化物酶体增殖物激活受体？活动将肥胖与脂肪组织炎症和胰岛素抵抗联系起来。我们的目标是提供机制的洞察Siah 2在控制PPAR？蛋白质水平、胰岛素敏感性和脂肪组织炎症。在具体目标1中，我们将测试 假设Siah 2依赖性修饰PPAR？限制了PPAR？通过增加PPAR？的配体依赖性蛋白酶体降解活性。具体目标2将评估Siah 2对脂肪组织炎症的影响。在具体的目标3，我们将测试的假设，Siah 2在脂肪细胞调节全身胰岛素敏感性通过调节过氧化物酶体增殖物激活受体？活性和脂肪和非脂肪组织之间的脂质分配。总之，这些研究将提供新的见解之间的关系？活性和脂肪组织在调节胰岛素敏感性中的作用，并将推进我们的目标，确定是否泛素-蛋白酶体系统在肥胖相关的胰岛素抵抗和2型糖尿病的治疗中代表一种新的治疗靶点。