Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

• 批准号: 9116816
• 负责人: JONATHAN BOGAN
• 金额: $ 37.46万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116816
• 关键词: ACBD3 gene; Accounting; Acetylation; Acute; Adipocytes; Adipose tissue; Affect; Animals; Binding; Bypass; Cell membrane; Cell surface; Cells; Cleaved cell; Complex; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endosomes; Energy Metabolism; Fasting; Fatty acid glycerol esters; GLUT 4 protein; GLUT4 gene; Genetic Predisposition to Disease; Glucose; Glucose Transporter; Goals; Golgi Apparatus; Grant; Half-Life; Health; Hormones; Hypertension; Impairment; Individual; Insulin; Insulin Resistance; Intracellular Membranes; Knockout Mice; Lead; Lipoproteins; Location; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Movement; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Overnutrition; Pathogenesis; Pathway interactions; Peptide Hydrolases; Physiological; Physiology; Prevention; Process; Proteins; Proteolytic Processing; Recycling; Regulation; Role; Testing; Transgenic Mice; Transgenic Organisms; Vasopressins; Vesicle; Work; blood glucose regulation; glucose metabolism; glucose transport; glucose uptake; improved; in vivo; insight; insulin sensitivity; insulin signaling; novel strategies; prevent; protein complex; quadriceps muscle; response; sortilin; trafficking

 DESCRIPTION (provided by applicant): The regulation of glucose homeostasis is a complex process, which is disrupted in disease states such as type 2 diabetes. Insulin is the primary hormone regulating glucose homeostasis. Insulin stimulates glucose uptake in muscle and fat by causing the movement of GLUT4 glucose transporters out of intracellular membranes and to the cell surface. This effect of insulin is impaired in the setting of overnutrition, inactivity, ad genetic predisposition, resulting in insulin resistance and contributing to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that control the targeting of GLUT4 among intracellular membranes, and by which this targeting is modulated by insulin. Previous work by this project identified the TUG protein as a regulator of GLUT4 targeting and glucose uptake in muscle, as in fat, and showed that this mechanism controls energy expenditure in mice. The data support a model in which GLUT4 is specifically retained within cells not stimulated by insulin by a protein complex containing TUG. Insulin then mobilizes GLUT4, in part by triggering TUG endoproteolytic cleavage. Cleavage may coordinate the regulation of glucose uptake with other effects on physiology and metabolism, which can result from the action of proteins that are produced by cleavage or co-regulated with GLUT4. This project focuses on the cleavage mechanism itself, and on how the ability of insulin to stimulate cleavage may be modulated to control insulin sensitivity. Aim 1 will define the relationship between TUG-bound vesicles and the insulin-responsive GLUT4 storage vesicles, and will study how TUG interacts with vesicle proteins, particularly IRAP, and undergoes proteolytic cleavage. To understand the physiologic role of TUG in the regulation in muscle, we will create muscle-specific TUG knockout mice and study glucose homeostasis in these animals. Aim 2 will study how acetylation of the TUG protein affects insulin sensitivity. We will test the hypothesis that acetylation modulates the interaction of the TUG carboxyl terminus with ACBD3, a protein present at the Golgi matrix, to control the size of an insulin-responsive pool of GLUT4. We will further study if a sirtuin protein regulates this acetylation to control insulin sensitivity in muscle, using knockout mice. We anticipate that, together, these studies will result in an improved understanding of molecular mechanisms regulating glucose metabolism and energy expenditure, with implications for the prediction, prevention, and treatment of diabetes and the metabolic syndrome.

 描述（由适用提供）：葡萄糖稳态的调节是一个复杂的过程，在2型糖尿病等疾病状态中受到破坏。胰岛素是控制葡萄糖稳态的主要激素。胰岛素通过从细胞内膜和细胞表面引起Glut4葡萄​​糖转运蛋白的运动来刺激肌肉和脂肪中的葡萄糖摄取。胰岛素的这种作用在营养不良，无效，AD遗传易感性的情况下受到损害，从而导致胰岛素抵抗并有助于糖尿病的发展。因此，要了解代谢疾病的发病机理，有必要了解控制细胞内机制中GLUT4的分子机制，并通过胰岛素调节该靶向。该项目的先前工作将拖线蛋白确定为肌肉中的GLUT4靶向和葡萄糖摄取的调节剂，如脂肪中，并且表明该机制控制着小鼠的能量消耗。数据支持一个模型，其中特异性保留在未被含有拖线的蛋白质复合物刺激的细胞中。然后，胰岛素通过触发拖线内蛋白溶解裂解来动员GLUT4。裂解可以协调葡萄糖摄取的调节与对生理和代谢的其他影响，这可能是由于裂解产生的蛋白质的作用或与GLUT4共同调节的。该项目着重于切割机制本身，以及如何调节胰岛素刺激裂解的能力以控制胰岛素敏感性。 AIM 1将定义拖线结合的蔬菜与胰岛素反应性GLUT4储存蔬菜之间的关系，并将研究拖线与蔬菜蛋白（尤其是IRAP）的相互作用，并经历蛋白水解裂解。为了了解拖线在肌肉调节中的生理作用，我们将创建肌肉特异性的拖轮敲除小鼠并研究这些动物中的葡萄糖稳态。 AIM 2将研究TUG蛋白的乙酰化如何影响胰岛素敏感性。我们将检验以下假设：乙酰化调节拖线羧基末端与ACBD3的相互作用，ACBD3是Golgi基质中存在的蛋白质，以控制GLUT4的胰岛素反应池的大小。我们将进一步研究Sirtuin蛋白 使用基因敲除小鼠调节这种乙酰化以控制肌肉中的胰岛素敏感性。我们预计，总之，这些研究将提高人们对调节葡萄糖代谢和能量消耗的分子机制的了解，这对糖尿病和代谢综合征的预测，预防和治疗产生了影响。