Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

基本信息

批准号：
10452851
负责人：
JONATHAN BOGAN
金额：
$ 51.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10452851
关键词：
1-Phosphatidylinositol 3-Kinase 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 Glucose Transporter Goals Golgi Apparatus High Fat Diet Hormones Hypertension Impairment Individual Insulin Insulin Resistance Intracellular Membranes Lead Link Lipoproteins Mediating Membrane Metabolic Diseases Metabolic syndrome Modeling Molecular Mus Muscle Muscle Cells N-terminal Non-Insulin-Dependent Diabetes Mellitus Obesity 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

项目摘要

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.

抽象的葡萄糖稳态的调节是一个复杂的过程，在疾病状态下会被破坏，例如类型 2 糖尿病。胰岛素是调节葡萄糖稳态的主要激素。胰岛素刺激血糖通过动员含有 GLUT4 葡萄糖转运蛋白的细胞内囊泡来摄取肌肉和脂肪，该转运蛋白融合并将 GLUT4 插入细胞表面。这一过程的受损会导致胰岛素抵抗并导致糖尿病的发展。因此，了解代谢性疾病的发病机制有必要了解控制 GLUT4 运输的分子机制，并了解这种运输是如何进行的受胰岛素调节并破坏胰岛素抵抗。之前的工作将 TUG 蛋白确定为肌肉和脂肪细胞中 GLUT4 运输和葡萄糖摄取的主要调节因子。数据支持模型 TUG 介导未刺激细胞内特定囊泡中 GLUT4 的细胞内保留。胰岛素触发 TUG 内切蛋白水解裂解，将这些囊泡动员到细胞表面。 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 GLUT4 以及 TUG C 末端产物调节基因表达的作用。在胰岛素中抵抗个体，这种机制的损害可能导致代谢综合征和肥胖。然而，目前尚不清楚这种机制在胰岛素抵抗中如何受到影响，是否减弱了 TUG 裂解导致肌肉胰岛素抵抗，或者 TUG 裂解是否参与运动刺激葡萄糖摄取。同样，完整的 TUG 在胰岛素中保留 GLUT4 的分子机制反应性囊泡池尚不清楚。为了解决这些问题，将实现两个目标。目标 1 将表征肌肉特异性破坏的小鼠的胰岛素抵抗和葡萄糖稳态 TUG 或 TUG 内蛋白水解裂解，并将研究该途径在运动诱导中的潜在作用葡萄糖摄取。目标 2 将研究 TUG 捕获含有 GLUT4 的囊泡的分子机制。胰岛素反应池，并且通过该池可以在胰岛素抵抗状态下改变该过程。我们预计总之，这些研究将加深对葡萄糖代谢和能量的了解支出，对糖尿病和代谢综合征的预防和治疗具有影响。