Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

• 批准号: 10592402
• 负责人: JONATHAN BOGAN
• 金额: $ 51.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592402
• 关键词: Address; Adipocytes; Affect; Aminopeptidase; Attenuated; Binding; C-terminal; Cardiovascular Diseases; Cell membrane; Cell surface; Cells; Complex; Data; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Energy Metabolism; Equilibrium; Exercise; Fasting; Fatty acid glycerol esters; Functional disorder; GLUT 4 protein; Gene Expression; Genetic Transcription; Glucose Transporter; Goals; Golgi Apparatus; High Fat Diet; Homeostasis; Hormones; Hypertension; Impairment; Individual; Insulin; Insulin Resistance; Intracellular Membranes; Link; Lipoprotein Receptor; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Muscle; Muscle Cells; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PIK3CG gene; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Physiological; Prevention; Process; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Stroke; Testing; Thermogenesis; Vasopressins; Vesicle; Work; attenuation; blood glucose regulation; fatty acid oxidation; fatty acylation; glucose metabolism; glucose uptake; improved; in vivo; insulin signaling; lipid metabolism; novel strategies; prevent; sortilin; syntaxin; syntaxin A; trafficking

Abstract 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 that regulates glucose homeostasis. Insulin stimulates glucose uptake in muscle and fat by mobilizing intracellular vesicles containing GLUT4 glucose transporters, which fuse and insert GLUT4 at the cell surface. Impairment of this process results in insulin resistance and contributes to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that control GLUT4 trafficking, and to understand how this trafficking is modulated by insulin and disrupted in insulin resistance. Previous work identified the TUG protein as a major regulator of GLUT4 trafficking and glucose uptake in muscle and fat cells. The data support a model in which TUG mediates the intracellular retention of GLUT4 in specific vesicles within unstimulated cells. Insulin triggers TUG endoproteolytic cleavage to mobilize these vesicles to the cell surface. TUG cleavage coordinates glucose uptake with other physiologic effects, resulting from the action of proteins that co-traffic with GLUT4, as well as from action of the TUG C-terminal product to modulate gene expression. In insulin resistant individuals, impairment of this mechanism may contribute to the metabolic syndrome and obesity. Yet, it remains unknown how this mechanism is affected in insulin resistance, whether attenuated TUG cleavage causes insulin resistance in muscle, or whether TUG cleavage participates in exercise-stimulated glucose uptake. As well, the molecular mechanisms by which intact TUG retains GLUT4 in an insulin- responsive pool of vesicles are not understood. To address these questions, two Aims will be undertaken. Aim 1 will characterize insulin resistance and glucose homeostasis in mice with muscle-specific disruption of TUG or of TUG endoproteolytic cleavage, and will study the potential role of this pathway in exercise-induced glucose uptake. Aim 2 will study molecular mechanisms by which TUG traps GLUT4-containing vesicles in an insulin-responsive pool, and by which this process may be altered in insulin-resistant states. We anticipate that, together, these studies will result in an improved understanding of glucose metabolism and energy expenditure, with implications for the prevention and treatment of diabetes and the metabolic syndrome.

摘要 葡萄糖稳态的调节是一个复杂的过程，其在疾病状态中被破坏，例如 2糖尿病.胰岛素是调节葡萄糖稳态的主要激素。胰岛素刺激葡萄糖 通过动员含有GLUT 4葡萄糖转运蛋白的细胞内囊泡， 并在细胞表面插入GLUT 4。这一过程的损害导致胰岛素抵抗，并有助于 糖尿病的发展。因此，了解代谢性疾病的发病机制， 了解控制GLUT 4运输的分子机制，并了解这种运输如何 受胰岛素调节并破坏胰岛素抵抗。以前的工作确定TUG蛋白是一种 肌肉和脂肪细胞中GLUT 4运输和葡萄糖摄取的主要调节剂。数据支持一个模型， 该TUG介导GLUT 4在未刺激细胞内的特定囊泡中的细胞内滞留。胰岛素 触发TUG内切蛋白水解切割以将这些囊泡移动到细胞表面。TUG裂解 协调葡萄糖摄取与其他生理效应，这是由共同运输的蛋白质的作用引起的 与GLUT 4，以及从TUG C-末端产物的作用，以调节基因表达。胰岛素 抵抗个体，该机制的损伤可能导致代谢综合征和肥胖。 然而，这一机制在胰岛素抵抗中是如何受到影响的，无论是减弱TUG， 切割导致肌肉中的胰岛素抵抗，或者TUG切割是否参与运动刺激的 葡萄糖摄取同样，完整的TUG将GLUT 4保留在胰岛素受体中的分子机制， 囊泡的响应池尚不清楚。为了解决这些问题，将采取两个目标。 目的1将描述肌肉特异性破坏胰岛素抵抗和葡萄糖稳态的小鼠， TUG或TUG内蛋白水解裂解，并将研究这一途径在运动诱导的 葡萄糖摄取目的2将研究TUG捕获含GLUT 4的囊泡的分子机制， 胰岛素应答池，并且通过其可以在胰岛素抵抗状态下改变该过程。我们预计 总之，这些研究将导致对葡萄糖代谢和能量的更好理解， 这一研究结果表明，糖尿病和代谢综合征的预防和治疗是一个非常重要的问题。