Regulation of insulin sensitivity by TUG acetylation

描述（由申请人提供）：衰老与代谢性疾病患病率的显著增加相关，包括胰岛素抵抗和2型糖尿病，这有助于心血管风险、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还不清楚。Sirtuins包括一个依赖NAD+的赖氨酸去乙酰化酶家族，它与衰老和长寿的各个方面有关。这些蛋白质通过控制各种靶蛋白的乙酰化，将细胞能量状态偶联到不同的输出。这一提议将验证乙酰化通过控制细胞内胰岛素反应池中GLUT4葡萄糖转运体的数量直接调节胰岛素敏感性的总体假设。数据支持一种模型，在这种模型中，GLUT4通过TUG被隔离在脂肪和肌肉细胞的细胞内，在缺乏胰岛素的情况下，将含有GLUT4的囊泡与高尔基基质连接起来。然后胰岛素引起TUG的位点特异性切割，将这些囊泡动员到细胞表面，促进葡萄糖的摄取。本提案的目的1将检验假设，即TUG在其羧基末端附近被乙酰化，并且这种乙酰化阻止了胰岛素反应池中含有glut4的囊泡的隔离。将对老年啮齿动物的TUG乙酰化是否增加进行测试。目的2将研究TUG的乙酰化如何控制其与特定高尔基基质蛋白的相互作用。将要测试的假设是，通过改变TUG与高尔基基质的相互作用，乙酰化阻止了含有glut4的小泡被困在一个池子里，而这个池子可以被胰岛素信号调动起来。目的3将验证一种假设，即特定的sirtui结合TUG并降低其乙酰化，以响应细胞NAD+浓度，从而增强胰岛素敏感性。预计这些目标的实现将提供新的理解，衰老如何通过对细胞能量状态和蛋白质乙酰化的影响与胰岛素敏感性的降低直接相关。这一认识将阐明与年龄有关的代谢性疾病的发病机制，对预防和治疗具有潜在的意义。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，导致大量发病率和死亡率。本文提出的研究将探讨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。

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.