Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity

描述(由申请人提供)： 巨噬细胞(MP)已被证明在肥胖开始时可渗入脂肪组织，是导致和维持肥胖的主要成分之一，但MPS在脂肪中的表型和代谢状态尚不清楚。在脂肪组织中，MPS随着肥胖的增加而积累脂质，类似于MPS在动脉粥样硬化病变中形成富含胆固醇的泡沫细胞的过程，众所周知，MPS在斑块的形成中扮演着类似的核心角色。通过代谢组学，我目前的研究和我们团队的工作表明，肥胖会对肌肉线粒体施加持续的脂肪负担，导致氧化和三羧酸循环(TCA)循环活动之间的不匹配。这种脱节导致不完全脂肪酸(FA)氧化，从而损害肌肉对胰岛素的敏感性和葡萄糖代谢。尽管肥胖和炎症之间存在着强烈的联系，但人们对线粒体代谢在MP生物学中的作用以及肥胖脂肪组织中的MPS是否处于类似的线粒体失调状态知之甚少。目前的应用通过研究FA诱导的MPS中(-氧化和线粒体功能的变化)来解决这一关键差距。我的中心假设是，MP线粒体功能的紊乱推动了肥胖症患者的局部和/或全身炎症反应。具体地说，MP脂质负担可能导致不完全氧化和线粒体应激，这反过来又会促进炎症和肥胖。我计划在MP细胞系、原代MPS和骨髓移植后肥胖的小鼠模型中测试中心假说并解决这一应用的总体目标，以确定在这些目标中MP特异性基因在脂肪组织中表达的贡献。1：MPS的脂质负荷导致线粒体脂肪酸氧化失调。2：FAs的线粒体加工是驱动MP炎症反应所必需的。3：体内MP脂摄取减少会阻碍局部炎症信号的形成，从而导致肥胖。我的长期目标是成为一名研究员，专注于炎症和脂肪代谢的十字路口肥胖的发病机制。阐明FA代谢在MP中的作用是重要的，因为MPS驱动的炎症反应的阐述对于肥胖的形成至关重要。该项目的结果将对肥胖研究领域产生巨大影响，因为人们对MP中的线粒体新陈代谢知之甚少。

DESCRIPTION (provided by applicant): Macrophages (MP) have been demonstrated to infiltrate adipose tissue at the onset of obesity and are one of the primary components contributing to and perpetuating obesity, but the phenotype and metabolic status of MPs in adipose remains unknown. In fat tissue MPs accumulate lipids as obesity increases similar to the formation of MPs into cholesterol-laden foam cells in an atherosclerotic lesion, where MPs are known to play a similar central role in the formation of plaques. Through metabolomic profiling, my current research and work from our group has shown that obesity imposes a persistent lipid burden on muscle mitochondria, resulting in a mismatch between (-oxidation and tricarboxylic acid cycle (TCA) cycle activity. This disconnect results in incomplete fatty acid (FA) (-oxidation which impairs muscle insulin sensitivity and glucose metabolism. Although strong links between obesity and inflammation exist, little is known about the role of mitochondrial metabolism in MP biology and whether MPs in obese adipose tissue are in a similar state of mitochondrial dysregulation. The current application addresses this critical gap by investigating FA-induced alterations in (-oxidation and mitochondrial function in MPs. It is my central hypothesis that perturbations in MP mitochondrial function drive local and/or systemic inflammatory responses in obesity. Specifically, MP lipid burden likely results in incomplete (-oxidation and mitochondrial stress, which in turn promotes inflammation and obesity. I plan to test the central hypothesis and address the overall objective of this application in MP cell lines, primary MPs, and in obese mouse models after bone marrow transplantation to determine the contribution of MP-specific gene expression in adipose tissue in these aims. 1: Lipid Loading of MPs Results in Dysregulated Mitochondrial Oxidation of Fatty Acids. 2: Mitochondrial Processing of FAs is Necessary to Drive the MP Inflammatory Response. 3: Decreasing MP Lipid Uptake in vivo Will Blunt the Formation of Local Inflammatory Signals and Obesity. My long term goal is to become a researcher focusing on the pathogenesis of obesity at the crossroads of inflammation and lipid metabolism. Clarifying the role of FA metabolism in the MP is important because the elaboration of the inflammatory response driven by MPs is essential to the formation of obesity. The outcomes of this project will have a dramatic impact on the field of obesity research because little is known about mitochondrial metabolism in the MP.