Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

基本信息

批准号：
10161017
负责人：
JONATHAN BOGAN
金额：
$ 16.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161017
关键词：
1-Phosphatidylinositol 3-Kinase Address Adipocytes Affect Attenuated Binding Biochemical Biology Body Composition Body Weight C-terminal Cell Nucleus Cell Respiration Cell membrane Cell surface Cells Complex Data Development Diabetes Mellitus Disease Electron Microscopy Endocytosis Endosomes Energy Metabolism Exocytosis Fatty acid glycerol esters GLUT4 gene Gene Expression Genetic Predisposition to Disease Glucose Glucose Transporter Glycogen Goals Golgi Apparatus Health Hormones Human Hypertension Image Impairment Individual Insulin Insulin Resistance Intracellular Membranes Knockout Mice Lead Learning Link Lipids Location Mediating Membrane Metabolic Metabolic Diseases Metabolic syndrome Methods Microscopy Modeling Molecular Movement Muscle Muscle Cells Mutagenesis Mutation Non-Insulin-Dependent Diabetes Mellitus Obesity Overnutrition Pathogenesis Pathway interactions Peptide Hydrolases Peptides Physiological Physiology Plasma Prevention Process Proteins Proteolysis Proteolytic Processing Regulation Site Specific qualifier value Subcellular structure Testing Tissues Triglycerides Vasopressins Vesicle Work blood glucose regulation glucose metabolism glucose uptake improved in vivo knockout animal novel strategies prevent sortilin syntaxin syntaxin 6 syntaxin A syntaxin binding protein 1 trafficking

项目摘要

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 causing the movement of intracellular membranes containing GLUT4 glucose transporters, which fuse and insert GLUT4 at the cell surface. This effect of insulin is impaired in the setting of overnutrition, inactivity, and 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 specify the trafficking of GLUT4 among intracellular membranes, and by which this trafficking is modulated by insulin and disrupted in insulin resistance. Previous work by this project 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, together with selected other proteins, in specific membrane vesicles within unstimulated cells. Insulin then mobilizes these vesicles by triggering TUG endoproteolytic cleavage. Cleavage coordinates glucose uptake with other physiologic effects, resulting from the action of proteins that are co-regulated with GLUT4 by this mechanism, as well as with possible effects on energy expenditure. In insulin resistant individuals, alterations in this membrane trafficking mechanism may contribute to multiple aspects of the metabolic syndrome. Yet, it remains unknown where TUG and GLUT4 are localized in cells, how this localization is affected in insulin resistance, and whether attenuated TUG cleavage can cause insulin resistance in vivo. To address these questions, three Aims will be undertaken. Aim 1 will characterize how TUG is able to trap the GLUT4-containing vesicles in unstimulated cells, and how it maintains these vesicles in an insulin-responsive configuration. Aim 2 will study the location and mechanism by which TUG anchors these vesicles to intracellular structures, and how this may be affected in insulin resistance. . Aim 3 will study the importance of TUG proteolysis in muscle for overall insulin action and glucose homeostasis. 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.

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下，该过程会受到干扰。胰岛素是调节葡萄糖稳态的主要激素。胰岛素通过引起含有 GLUT4 葡萄糖转运蛋白的细胞内膜运动来刺激肌肉和脂肪中的葡萄糖摄取，该转运蛋白将 GLUT4 融合并插入细胞表面。在营养过剩、缺乏活动和遗传倾向的情况下，胰岛素的这种作用会受到损害，导致胰岛素抵抗并导致糖尿病的发生。因此，为了了解代谢疾病的发病机制，有必要了解 GLUT4 在细胞内膜之间运输的分子机制，以及这种运输受胰岛素调节并在胰岛素抵抗中被破坏的分子机制。该项目之前的工作确定了 TUG 蛋白是肌肉和脂肪细胞中 GLUT4 运输和葡萄糖摄取的主要调节因子。该数据支持这样一种模型，其中 TUG 介导 GLUT4 以及选定的其他蛋白质在未刺激细胞内的特定膜囊泡中的细胞内保留。然后胰岛素通过触发 TUG 内切蛋白水解裂解来动员这些囊泡。裂解协调葡萄糖摄取与其他生理效应，这些生理效应是由通过这种机制与 GLUT4 共同调节的蛋白质的作用引起的，并且可能对能量消耗产生影响。在胰岛素抵抗个体中，这种膜运输机制的改变可能导致代谢综合征的多个方面。然而，目前尚不清楚 TUG 和 GLUT4 在细胞中的定位、这种定位在胰岛素抵抗中如何受到影响，以及 TUG 裂解减弱是否会导致体内胰岛素抵抗。为了解决这些问题，将实现三个目标。目标 1 将描述 TUG 如何能够在未刺激的细胞中捕获含有 GLUT4 的囊泡，以及它如何将这些囊泡维持在胰岛素响应配置中。目标 2 将研究 TUG 将这些囊泡锚定到细胞内结构的位置和机制，以及这如何影响胰岛素抵抗。。目标 3 将研究肌肉中 TUG 蛋白水解对于整体胰岛素作用和葡萄糖稳态的重要性。我们预计，这些研究将共同提高对调节葡萄糖代谢和能量消耗的分子机制的理解，对糖尿病和代谢综合征的预测、预防和治疗具有影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.

DOI：
10.2337/db16-0243
发表时间：
2016-09
期刊：
Diabetes
影响因子：
7.7
作者：
Tol MJ;Ottenhoff R;van Eijk M;Zelcer N;Aten J;Houten SM;Geerts D;van Roomen C;Bierlaagh MC;Scheij S;Hoeksema MA;Aerts JM;Bogan JS;Dorn GW 2nd;Argmann CA;Verhoeven AJ
通讯作者：
Verhoeven AJ