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，该领域的努力主要集中在线粒体功能障碍与肥胖、胰岛素抵抗和 2 型糖尿病 (T2DM) 的病因学之间的联系。大量研究表明，此类代谢紊乱伴随着线粒体含量减少、线粒体呼吸能力受损、氧化应激加剧、氧化受损，从而改变全身脂质和葡萄糖代谢。与此同时，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的改变和脂联素的产生密切相关。在 通过本提案中概述的研究，我们将更好地定义线粒体功能对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动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作的效果，并对导致全身代谢益处和脂联素诱导的模型之间的共同点和独特特征进行分类来解决这些问题。 我们将以分层方式解决这个问题，重点关注白色脂肪细胞中线粒体程序的广泛诱导物（目标 1），然后对线粒体活动进行更具体的操作（目标 2），其中我们采用两种关键线粒体蛋白（mitoNEET 和线粒体二羧酸载体）的功能获得和丧失模型。这将使我们能够以非常有针对性的方式有效地操纵线粒体活动。在最后一个目标（目标 3）中，我们将开发一个系统，使我们能够以高度可滴定的方式选择性地在脂肪细胞中选择性地急剧淘汰线粒体的整体功能。结合起来，这些研究使我们能够仔细剖析线粒体功能改变对脂联素产生和白色脂肪细胞整体细胞生理学的影响。而线粒体功能在棕色脂肪细胞中的既定作用是 值得赞赏的是，我们的数据表明，白色脂肪细胞中线粒体功能的相关性被错误地低估了。我们已经生成了一个独特的工具集，使我们能够系统地解决“线粒体功能障碍”的问题，并且事实上，帮助我们系统地定义“功能障碍”一词。我们还希望更好地了解脂联素产生和释放的机制。基于 根据我们的初步数据，我们坚信线粒体活动在此过程中起着至关重要的作用。我们的研究结果将帮助我们从机制上定义为什么脂肪细胞通过测量线粒体活性来调节脂联素释放到循环中，从而更好地了解脂联素在系统中的作用。