Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

• 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
• 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

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，在诸如2型糖尿病等疾病状态下受到破坏。胰岛素是调节葡萄糖稳态的主要激素。胰岛素通过导致含有GLUT4葡萄糖转运蛋白的细胞内膜的运动来刺激肌肉和脂肪的葡萄糖摄取，这些膜在细胞表面融合并插入GLUT4。胰岛素的这种作用在营养不良，不活跃和遗传易感性的环境中受到损害，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，有必要理解指定GLUT4在细胞内膜中运输的分子机制，并且通过胰岛素调节这种运输并在胰岛素抵抗中受到破坏。该项目的先前工作将拖线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剂。数据支持一个模型，其中TUG在未刺激的细胞内的特定膜囊泡中介导GLUT4的细胞内保留率以及选定的其他蛋白质。然后，胰岛素通过触发拖线内蛋白溶解裂解来动员这些囊泡。裂解与其他生理作用坐在葡萄糖吸收中，这是由于蛋白质与GLUT4通过该机制共同调节的作用，以及对能量消耗的可能影响。在胰岛素耐药的个体中，这种膜运输机制的改变可能有助于代谢综合征的多个方面。然而，仍然未知拖线和glut4位于细胞中的位置，该定位如何在胰岛素抵抗中影响，以及减弱的拖线裂解是否会在体内引起胰岛素抵抗。为了解决这些问题，将实现三个目标。 AIM 1将表征Tug如何在未刺激的细胞中捕获含GLUT4的囊泡，以及如何将这些囊泡维持在胰岛素反应性构型中。 AIM 2将研究拖线将这些囊泡锚定在细胞内结构以及在胰岛素抵抗中如何影响的位置和机制。 。 AIM 3将研究拖船蛋白水解在肌肉中的重要性，对整体胰岛素作用和葡萄糖稳态。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。

项目成果

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