Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity

炎症、胰岛素抵抗中的巨噬细胞线粒体应激

• 批准号: 7479191
• 负责人: Liza Makowski-Hayes
• 金额: $ 8.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479191
• 关键词: Activity Cycles; Address; Adipocytes; Adipose tissue; Arterial Fatty Streak; Arthritis; Asthma; Automobile Driving; Biology; Bone Marrow Transplantation; Cardiovascular Diseases; Cell Line; Cells; Cholesterol; Citric Acid Cycle; Development Plans; Diabetes Mellitus; Diet; Dyslipidemias; Endothelial Cells; Ensure; Epidemic; Fatty Acids; Fatty acid glycerol esters; Foam Cells; Foundations; Functional disorder; Funding; Future; Gene Expression; Goals; Grant; Health Benefit; Hepatocyte; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intracellular Accumulation of Lipids; Knowledge; Link; Lipids; Malignant Neoplasms; Medical; Mentors; Metabolic; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Muscle; Muscle Mitochondria; Obesity; Outcome; Overnutrition; Pathogenesis; Pathology, Other; Pathway interactions; Phenotype; Play; Process; Public Health; Rate; Reactive Oxygen Species; Research; Research Personnel; Research Proposals; Role; Signal Transduction; Stress; Testing; Tissues; Training; Universities; Work; Writing; career; cell type; cytokine; experience; fatty acid metabolism; fatty acid oxidation; functional disability; glucose metabolism; in vivo; insulin sensitivity; lipid metabolism; macrophage; metabolomics; mouse model; oxidation; professor; skills; social; uptake

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.

描述（由申请人提供）： 巨噬细胞 (MP) 已被证明在肥胖发生时会浸润脂肪组织，是导致和持续肥胖的主要成分之一，但脂肪中 MP 的表型和代谢状态仍不清楚。随着肥胖的增加，MP 在脂肪组织中积累脂质，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，已知 MP 在斑块的形成中发挥类似的核心作用。通过代谢组学分析，我目前的研究和我们小组的工作表明，肥胖会给肌肉线粒体带来持续的脂质负担，导致 氧化和三羧酸循环 (TCA) 循环活动之间不匹配。这种脱节导致不完全脂肪酸 (FA) 氧化，从而损害肌肉胰岛素敏感性和葡萄糖代谢。 肥胖和炎症之间存在着某种联系，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 MP 是否处于类似的线粒体失调状态知之甚少。当前的应用通过研究 FA 诱导的 MP 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 中的扰动 线粒体功能驱动肥胖症的局部和/或全身炎症反应。具体来说，MP 脂质负担可能导致不完全氧化和线粒体应激，进而促进炎症和肥胖。我计划测试中心假设并解决该应用在 MP 细胞系、原代 MP 和骨髓移植后肥胖小鼠模型中的总体目标，以确定 MP 特异性基因在脂肪组织中的表达就是为了实现这些目标。图 1：MP 的脂质负载导致脂肪酸线粒体氧化失调。 2：FA 的线粒体处理对于驱动 MP 炎症反应是必要的。 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 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。阐明 FA 代谢在 MP 中的作用非常重要，因为 MP 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 中的线粒体代谢知之甚少。