Regulation of insulin sensitivity by TUG acetylation

通过 TUG 乙酰化调节胰岛素敏感性

• 批准号: 8516944
• 负责人: JONATHAN BOGAN
• 金额: $ 19.67万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516944
• 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

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.

描述（由申请人提供）：衰老与代谢性疾病（包括胰岛素抵抗和2型糖尿病）的患病率显著增加相关，这会导致心血管风险、肾脏疾病、视网膜病变和其他合并症。衰老如何影响胰岛素在脂肪和肌肉中的作用尚不清楚。Sirtuins包含NAD+依赖性赖氨酸脱乙酰酶家族，其涉及衰老和长寿的各个方面。这些蛋白质通过控制各种靶蛋白的乙酰化将细胞能量状态与不同的输出耦合。该提案将测试以下总体假设：乙酰化通过控制细胞内胰岛素响应池中GLUT 4葡萄糖转运蛋白的数量来直接调节胰岛素敏感性。数据支持一个模型，其中GLUT4被隔离在细胞内的脂肪和肌肉细胞的TUG，连接GLUT4含有囊泡的高尔基体基质在胰岛素的情况下。然后，胰岛素引起TUG的位点特异性切割，以将这些囊泡动员到细胞表面并促进葡萄糖摄取。本提案的目的1将检验TUG在其羧基末端附近被乙酰化的假设，并且该乙酰化防止了含GLUT 4的囊泡在胰岛素应答池中的螯合。将检测老年啮齿动物中TUG乙酰化是否增加。目的二研究乙酰化修饰对TUG与高尔基体基质蛋白相互作用的影响。将要检验的假设是，通过改变TUG与高尔基体基质的相互作用，乙酰化防止了含有GLUT 4的囊泡被捕获在可以响应于胰岛素信号而被动员的池中。目的3将测试特定sirtui结合TUG并响应于细胞NAD+浓度降低其乙酰化，从而增强胰岛素敏感性的假设。预计这些目标的实现将提供对衰老如何通过对细胞能量状态和蛋白质乙酰化的影响直接与胰岛素敏感性降低相关的新理解。这一认识将有助于阐明年龄相关代谢性疾病的发病机制，并对预防和治疗具有潜在意义。公共卫生意义：几乎三分之一的老年人患有糖尿病，四分之三的人患有胰岛素抵抗或糖尿病。这些代谢异常是一个巨大的公共卫生负担，导致大量的发病率和死亡率。本文提出的研究将调查衰老如何促进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。