Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity

描述（由申请人提供）： 已证实，在肥胖症的发病时，巨噬细胞（MP）浸润脂肪组织，并且是促成和维持肥胖症的主要组分之一，但脂肪中MP的表型和代谢状态仍然未知。在脂肪组织中，随着肥胖增加，MP积累脂质，类似于在动脉粥样硬化病变中MP形成充满胆固醇的泡沫细胞，其中已知MP在斑块形成中发挥类似的中心作用。通过代谢组学分析，我目前的研究和我们小组的工作表明，肥胖对肌肉线粒体施加了持续的脂质负担，导致β-氧化和三羧酸循环（TCA）循环活性之间的不匹配。这种断开导致不完全的脂肪酸（FA）氧化，损害肌肉胰岛素敏感性和葡萄糖代谢。虽然肥胖和炎症之间存在密切的联系，线粒体代谢在MP生物学中的作用以及肥胖脂肪组织中的MP是否处于类似的线粒体失调状态，目前知之甚少。本申请通过研究FA诱导的MP中β-氧化和线粒体功能的改变来解决这一关键差距。我的中心假设是MP线粒体功能的扰动驱动肥胖症的局部和/或全身炎症反应。具体而言，MP脂质负担可能导致不完全的β-氧化和线粒体应激，这反过来又促进炎症和肥胖。我计划测试中心假设，并解决这个应用程序的总体目标，在MP细胞系，原代MP，并在骨髓移植后的肥胖小鼠模型，以确定在这些目标中的MP特异性基因表达在脂肪组织中的贡献。1：MP的脂质负荷导致脂肪酸的线粒体氧化失调。2：线粒体对FA的加工是驱动MP炎症反应所必需的。3：减少体内MP脂质摄取将减弱局部炎症信号和肥胖的形成。我的长期目标是成为一名研究人员，专注于炎症和脂质代谢十字路口的肥胖发病机制。澄清FA代谢在MP中的作用是重要的，因为MP驱动的炎症反应的阐述对于肥胖的形成是必不可少的。该项目的结果将对肥胖研究领域产生巨大影响，因为对MP中的线粒体代谢知之甚少。

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.