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: 8208231
• 负责人: Liza Makowski-Hayes
• 金额: $ 23.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208231
• 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; Disease; 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; National Heart, Lung, and Blood Institute; Obese Mice; Obesity; Outcome; Outcomes Research; Overnutrition; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Process; Public Health; Reactive Oxygen Species; Research; Research Personnel; Research Proposals; Role; Signal Transduction; Stress; Testing; Tissues; Training; Universities; Work; Writing; career; career development; cell type; combat; cytokine; experience; fatty acid metabolism; fatty acid oxidation; functional disability; glucose metabolism; in vivo; insulin sensitivity; lipid disorder; lipid metabolism; macrophage; metabolomics; mouse model; oxidation; professor; skills; social; treatment strategy; 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）已被证明在肥胖开始时浸润脂肪组织，是导致肥胖症和永久性肥胖的主要成分之一，但是脂肪中MPS的表型和代谢状态仍然未知。在脂肪组织中，MP会积聚脂质，因为肥胖的增加与动脉粥样硬化病变中MPS形成胆固醇泡沫细胞的形成相似，在该病变中，众所周知，MPS在斑块形成中起着相似的中心作用。通过代谢组分析，我目前的研究和来自小组的工作表明，肥胖对肌肉线粒体施加了持久的脂质负担，导致（ - 氧化和三羧酸周期（TCA）循环活动之间的不匹配。在肥胖和炎症之间存在，对线粒体代谢在MP生物学中的作用几乎没有知识，以及肥胖的脂肪组织中的MP是否处于类似的线粒体状态状态，目前的施用解决了这种关键的差距，从而通过研究FA诱导的（ - 氧化和线粒体中的Mypoth in Contranter in Contrant in Contrant in Contranter in Contrant in Contranter in Contrant in Contrant in Contrant in Contranter in Contrant in Contrant in Contrant in Contrant in Contrant in Contrant in Contrult in Myposh in Myps in Myps。线粒体功能在肥胖症中驱动局部和/或全身性炎症反应。我计划测试中心假设，并解决此应用在骨髓移植后的MP细胞系，原代MP和肥胖小鼠模型中的总体目标，以确定这些目标中MP特异性基因表达在脂肪组织中的贡献。 1：MPS的脂质负荷导致脂肪酸的线粒体氧化失调。 2：FAS的线粒体处理对于推动MP炎症反应是必要的。 3：减少体内MP脂质摄取将钝化局部炎症信号和肥胖。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的十字路口的肥胖症发病机理。阐明FA代谢在MP中的作用很重要，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，因为对MP中的线粒体代谢知之甚少。