Regulation of insulin sensitivity by TUG acetylation

通过 TUG 乙酰化调节胰岛素敏感性

基本信息

批准号：
8386145
负责人：
JONATHAN BOGAN
金额：
$ 24.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386145
关键词：
Acetylation Adipocytes Adipose tissue Affect Age Aging Binding Biochemical Cell membrane Cell surface Cells Comorbidity Control Animal Coupled Data Deacetylation Development Diabetes Mellitus Diet Elderly Enzymes Family Family member Fatty acid glycerol esters GLUT4 gene Genetic Glucose Glucose Transporter Golgi Apparatus Individual Insulin Insulin Resistance Kidney Diseases Kinetics Knowledge Light Link Longevity Lysine Maps Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Microscopy Mitochondria Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Mutate Non-Insulin-Dependent Diabetes Mellitus Obesity Output Overnutrition Pathogenesis Physical activity Physiological Population Post-Translational Protein Processing Prediabetes syndrome Prevalence Prevention Prevention therapy Protein Acetylation Protein Binding Protein Isoforms Proteins Public Health RNA Interference Regulation Research Retinal Diseases Rodent Role Sirtuins Site Specificity Surface Techniques Testing Vesicle Work adipocyte differentiation age related aged basal insulin cardiovascular risk factor glucose uptake inhibitor/antagonist insight insulin sensitivity insulin signaling knockout animal mortality mutant overexpression prevent response

项目摘要

DESCRIPTION (provided by applicant): Aging is associated with a marked increase in the prevalence of metabolic disease, including insulin resistance and type 2 diabetes, which contributes to cardiovascular risk, kidney disease, retinopathy, and other comorbidities. How aging affects insulin action in fat and muscle is not well understood. Sirtuins comprise a family of NAD+-dependent lysine deacetylases, which are implicated in various aspects of aging and longevity. These proteins couple cellular energy status to distinct outputs by controlling the acetylation of various target proteins. This proposal will test the overall hypothesis that acetylation regulates insulin sensitivity directly, by controlling the number of GLUT4 glucose transporters that reside in an intracellular, insulin-responsive pool. Data support a model in which GLUT4 is sequestered intracellularly in fat and muscle cells by TUG, which links GLUT4-containing vesicles to the Golgi matrix in the absence of insulin. Insulin then causes site-specifi cleavage of TUG to mobilize these vesicles to the cell surface and to promote glucose uptake. Aim 1 of the present proposal will test the hypothesis that TUG is acetylated near its carboxyl terminus, and that this acetylation prevents the sequestration of GLUT4-containing vesicles in an insulin-responsive pool. It will be tested if TUG acetylation is increased in aged rodents. Aim 2 will study how acetylation of TUG controls its interaction with specific Golgi matrix proteins. The hypothesis that will be tested is that, by altering the interaction of TUG with the Golgi matrix, acetylation prevents the trapping of GLUT4-containing vesicles in a pool that can be mobilized in response to an insulin signal. Aim 3 will test the hypothesis that a particular sirtui binds TUG and reduces its acetylation in response to cellular NAD+ concentrations, thus enhancing insulin sensitivity. It is anticipated that accomplishment of these Aims will provide new understanding of how aging is linked directly to reductions in insulin sensitivity, through effects on cellular energy status and protein acetylation. This understanding will shed light on the pathogenesis of age-related metabolic diseases, with potential implications for prevention and treatment. Public Health Significance: Almost one-third of elderly individuals have diabetes, and three-quarters have insulin resistance or diabetes. These metabolic abnormalities are an enormous public health burden, which contribute to substantial morbidity and mortality. The research proposed here will investigate how aging contributes to the development of insulin resistance in fat and muscle, which is a critical component in the pathogenesis of diabetes in the elderly population. PUBLIC HEALTH RELEVANCE: This project will study how aging affects insulin-responsive glucose uptake in fat and muscle, and will identify new mechanisms for the control of insulin sensitivity. The results of this work will shed light on how insulin resistance develops and leads to type 2 diabetes in the elderly, will have importance for the prevention and treatment of age-related metabolic disease.

描述（由申请人提供）：衰老与代谢疾病患病率显着增加相关，包括胰岛素抵抗和 2 型糖尿病，这会导致心血管风险、肾脏疾病、视网膜病变和其他合并症。衰老如何影响脂肪和肌肉中的胰岛素作用尚不清楚。 Sirtuins 包含 NAD+ 依赖性赖氨酸脱乙酰酶家族，与衰老和长寿的各个方面有关。这些蛋白质通过控制各种目标蛋白质的乙酰化将细胞能量状态与不同的输出结合起来。该提案将检验乙酰化通过控制细胞内胰岛素反应池中 GLUT4 葡萄糖转运蛋白的数量来直接调节胰岛素敏感性的总体假设。数据支持这样一种模型，其中 GLUT4 通过 TUG 被隔离在细胞内的脂肪和肌肉细胞中，在没有胰岛素的情况下，TUG 将含有 GLUT4 的囊泡连接到高尔基体基质。然后胰岛素引起 TUG 的位点特异性裂解，将这些囊泡动员到细胞表面并促进葡萄糖摄取。本提案的目标 1 将检验以下假设：TUG 在其羧基末端附近被乙酰化，并且这种乙酰化可防止含有 GLUT4 的囊泡被隔离在胰岛素反应库中。将测试老年啮齿动物中 TUG 乙酰化是否增加。目标 2 将研究 TUG 的乙酰化如何控制其与特定高尔基体基质蛋白的相互作用。将要测试的假设是，通过改变 TUG 与高尔基体基质的相互作用，乙酰化可以防止将含有 GLUT4 的囊泡捕获在池中，而这些囊泡可以响应胰岛素信号而被动员。目标 3 将测试以下假设：特定的 Sirtui 结合 TUG 并响应细胞 NAD+ 浓度降低其乙酰化，从而增强胰岛素敏感性。预计这些目标的实现将通过对细胞能量状态和蛋白质乙酰化的影响，为衰老如何与胰岛素敏感性降低直接相关提供新的认识。这一认识将揭示与年龄相关的代谢疾病的发病机制，对预防和治疗具有潜在影响。公共卫生意义：近三分之一的老年人患有糖尿病，四分之三的老年人患有胰岛素抵抗或糖尿病。这些代谢异常是巨大的公共卫生负担，导致大量的发病率和死亡率。这里提出的研究将调查衰老如何导致脂肪和肌肉中胰岛素抵抗的发展，这是老年人糖尿病发病机制的关键组成部分。公共健康相关性：该项目将研究衰老如何影响脂肪和肌肉中胰岛素反应性葡萄糖的摄取，并将确定控制胰岛素敏感性的新机制。这项工作的结果将揭示老年人胰岛素抵抗如何发展并导致 2 型糖尿病，对于预防和治疗与年龄相关的代谢疾病具有重要意义。