White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin

白色脂肪组织生理学、线粒体功能和脂联素

• 批准号: 8557828
• 负责人: PHILIPP E SCHERER
• 金额: $ 46.43万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8557828
• 关键词: Adipocytes; Adipose tissue; Amyloid; Area; Attention; Biogenesis; Blood Circulation; Carbohydrates; Cardiovascular Diseases; Cataloging; Catalogs; Cell physiology; Data; Diet; Electron Transport; Etiology; FGF21 gene; Fatty acid glycerol esters; Functional disorder; Generic Drugs; Homeostasis; Insulin Resistance; Intervention; Lead; Link; Lipids; Mediating; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Mitochondrial Proteins; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outer Mitochondrial Membrane; Oxidative Stress; Pathway interactions; Phase; Physiology; Play; Process; Production; Protein Import; Protein Precursors; Proteins; Research Infrastructure; Role; Surveys; System; Testing; Vascular Endothelial Growth Factors; adiponectin; base; coping; cytochrome c oxidase; diabetic; dicarboxylate-binding protein; glucose metabolism; lipid metabolism; loss of function; mitochondrial dysfunction; mitochondrial membrane; mouse model; oxidation; programs; public health relevance; respiratory

DESCRIPTION (provided by applicant): Over the past decade, efforts in the field have focused on the connection between mitochondrial dysfunction and the etiology of obesity, insulin resistance and the progression of type 2 diabetes mellitus (T2DM). Numerous studies indicate that such metabolic disorders are accompanied by reduced mitochondrial content, compromised mitochondrial respiratory capacity, heightened oxidative stress, impaired -oxidation and, consequently, altered whole-body lipid and glucose metabolism. In parallel, both the production and the release of the adipokine adiponectin are frequently impaired as well. Our data indicate that altered mitochondrial activity and adiponectin production are tightly linked. In the studies outlined in this proposal, we will better define the impact of mitochondrial function o white adipose tissue physiology and establish which metabolic intermediates are the critical drivers connecting mitochondrial activity and adiponectin production. We propose to approach these questions by surveying the effects of a number of different manipulations of mitochondrial activity in adipocytes and cataloguing the common denominators and distinct features between the models that lead to systemic metabolic benefits and the induction of adiponectin. We will approach this in a hierarchical fashion by focusing on broad inducers of the mitochondrial program in the white adipocyte (Aim 1), followed by a more specific manipulation of mitochondrial activity (Aim 2) in which we employ gain and loss of function models of two critical mitochondrial proteins, mitoNEET and the mitochondrial dicarboxylate carrier. This will allow us to effectively manipulate mitochondrial activity in a very-targeted fashion. In the last aim (Aim 3, we will develop a system that will allow us to acutely phase out overall mitochondrial function selectively in adipocytes in a highly-titratable fashion. Combined, these studies enable us to carefully dissect the effects of altered mitochondrial function on adiponectin production and overall cellular physiology of the white adipocyte. While the established role of mitochondrial function in brown adipocytes is well appreciated, our data argues that the relevance of mitochondrial function in the white adipocyte has been mistakenly undervalued. We have generated a unique toolset that allows us to systematically approach the question of "mitochondrial dysfunction" and, in fact, helps us to methodically define the term "dysfunction". We also have the desire to better understand the mechanisms governing adiponectin production and release. Based upon our preliminary data, we strongly believe that mitochondrial activity plays an essential role in this process. Results from our studies will help us define mechanistically why adipocytes regulate adiponectin release into circulation by gauging mitochondrial activity, leading to a better teleological understanding of the role of adiponectin within the system.

描述（由申请人提供）：在过去的十年中，该领域的努力集中在线粒体功能障碍与肥胖，胰岛素抵抗的病因和2型糖尿病（T2DM）的进展之间的联系。大量研究表明，这种代谢性疾病伴随着降低的线粒体含量，线粒体呼吸能力损害，氧化应激升高，氧化受损，并改变了全身脂质和葡萄糖代谢。同时，脂肪因子脂联素的产生和释放也经常受到损害。我们的数据表明，线粒体活性改变和脂联素的产生紧密相关。在 在该提案中概述的研究中，我们将更好地定义线粒体功能o白色脂肪组织生理学的影响，并确定哪些代谢中间体是连接线粒体活性和脂联素产生的关键驱动因素。我们建议通过调查脂肪细胞中线粒体活性的多种不同操纵的影响，并分类共同点的效果，并在模型之间分类共同的分母以及导致全身代谢益处的模型和诱导脂联素之间的独特特征。 我们将通过层次的方式来解决这一目标，通过关注白色脂肪细胞中线粒体程序的广泛诱导剂（AIM 1），然后更具体地对线粒体活性进行操纵（AIM 2），在该操作中，我们采用了两个关键的线粒体蛋白，线粒体，线粒体和线粒体核心二甲酰胺二甲酰胺二甲酰胺的功能模型的增益和功能丧失。这将使我们能够以非常靶向的方式有效地操纵线粒体活动。在最后一个目标中（目标3，我们将开发一个系统，使我们能够以高度可观的方式在脂肪细胞中选择性地逐渐淘汰整体线粒体功能。结合在一起，这些研究使我们能够仔细地逐步剖析了线粒体功能改变的脂肪组素生产和整体细胞生理学的作用，同时是白色琼脂的整体生理学。我们的数据认为，在白色脂肪细胞中，线粒体功能的相关性已被错误地被低估了，我们已经产生了一个独特的工具集，使我们可以系统地接触“线粒体功能障碍”的问题，实际上，我们也可以将术语定义为“ distry”我们的初步数据，我们坚信线粒体活性在我们的研究中起着至关重要的作用，这将有助于我们从机械上定义脂肪细胞来定义脂肪素的释放，从而通过计量线粒体活性来循环，从而导致对系统在系统中的作用更好的目标理解。