Macrophage Mitochondrial Stress in Inflammation, Insulin Resistance & Obesity

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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.