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.

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