Control of Macrophage Metabolism by Oxidized Phospholipids - Implications in Obesity-associated Adipose Tissue Inflammation

Serbulea, Vlad, Pharmacology - School of Medicine, University of Virginia
Leitinger, Norbert, Department of Pharmacology, University of Virginia

Oxidative stress is a phenomenon that has been associated with nearly every disease known to man. The regulation of reduction and oxidation (redox) reactions is crucial to the survival of every organism. As such, many organisms have evolved numerous systems for sensing redox balance and maintaining homeostasis. Metabolic and inflammatory diseases such as diabetes, obesity, and atherosclerosis involve a causal redox imbalance. It is unclear whether the perceived redox imbalance associated with diseases causes or merely correlates with inflammation.
This dissertation attempts to address this question by studying redox regulation in adipose tissue macrophages during the development of obesity. The overarching hypothesis of this work is that lipid oxidation products, formed in adipose tissue during obesity, reprogram macrophages for inflammation. The focus of this research lies in interrogating the changes in macrophage metabolism and function brought on by oxidized phospholipids. This work attempts to summarize and explain the various nuances of macrophage redox balance at the cellular and molecular level.
Using a combination of mass spectrometry, flow cytometry, and extracellular flux analysis, this study uncovers new viewpoints in a controversial field. We obtained unexpected results, which redefine previous notions regarding adipose tissue macrophage polarization. In brief, this work provides evidence that a majority of resident adipose tissue macrophages are of the Mox macrophage polarization phenotype emphasizing antioxidant production. Furthermore, this work adds to a growing body of literature that macrophage metabolism can directly influence and determine macrophage function, paving the way for novel therapeutics targeting macrophage bioenergetics.

PHD (Doctor of Philosophy)
oxidative stress, macrophage, redox, diabetes, obesity
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