Regulation of insulin sensitivity by TUG acetylation

描述(申请人提供)：老龄化与代谢性疾病的发病率显著增加有关，包括胰岛素抵抗和2型糖尿病，后者会导致心血管疾病、肾脏疾病、视网膜病变和其他并存疾病。衰老如何影响脂肪和肌肉中的胰岛素作用还不是很清楚。Sirtuins包括一个依赖NAD的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不同目标蛋白的乙酰化，将细胞能量状态与不同的输出相结合。这项提议将通过控制细胞内胰岛素响应池中的GLUT4葡萄糖转运体的数量，来检验乙酰化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，即GLUT4通过TRAG将GLUT4隔离在脂肪和肌肉细胞内，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TRAG的定点裂解，将这些小泡动员到细胞表面，促进葡萄糖的摄取。本提案的目标1将检验这样的假设，即TUG在其羧基末端附近被乙酰化，并且这种乙酰化防止含有GLUT4的囊泡被隔离在胰岛素反应池中。这将在老年啮齿动物中测试是否增加了TRAG乙酰化。目的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GLUT4的囊泡被困在池中，该池可以响应胰岛素信号而被动员。目的3将验证这样一种假设，即特定的sirtui结合TRAG并减少其乙酰化，以响应细胞内NAD浓度，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，对衰老如何与胰岛素敏感性降低直接相关提供新的理解。这一认识将有助于阐明与年龄相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，导致相当大的发病率和死亡率。这里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，这是老年人口糖尿病发病机制中的一个关键组成部分。 公共卫生相关性：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。这项工作的结果将有助于阐明胰岛素抵抗是如何在老年人中发展并导致2型糖尿病的，对预防和治疗与年龄相关的代谢性疾病具有重要意义。

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.