In both mice and humans, low-grade chronic inflammation has emerged as a potential link between obesity, insulin resistance and cardiovascular disease. For instance, obesity results in a gradual increase (2-4-fold) in various inflammatory cytokines and chemokines in white adipose tissue (WAT). This increase in tissue inflammation, which is primarily observed in visceral WAT (epididymal WAT (eWAT) in mice), results from the recruitment and activation of innate and adaptive immune cells. In contrast, obese subcutaneous WAT (scWAT) seems to be resistant to the development of tissue inflammation. Although this resistance of scWAT to diet-induced inflammation is observed in both mice and humans, the cellular and molecular pathways that limit the inflammatory response in scWAT or exacerbate it in eWAT remain incompletely understood. This is an important question to address because studies dating back half a century have demonstrated that increases in visceral, but not subcutaneous, fat mass is associated with a higher risk of metabolic disease in humans. Although a number of cell types and molecules that contribute to adipose tissue inflammation have been identified, three fundamental questions remain unanswered. First, is the susceptibility of eWAT or the resistance of scWAT to developing obesity-associated inflammation an intrinsic property of adipocytes or do adipocyte extrinsic factors also contribute to depot specific inflammatory responses? Second, what factors restrain or limit the recruitment of inflammatory cells into obese scWAT? Third, what controls the susceptibility of eWAT to developing metabolic inflammation? In this application, we will elucidate adipocyte extrinsic factors that regulate susceptibility or resistance of eWAT or scWAT, respectively, to diet-induced inflammation, and the mechanisms by which these pathways contribute to the pathogenesis of obesity-induced metabolic dysfunction. This will be accomplished by employing an interdisciplinary approach that encompasses mouse genetics, molecular and cellular biology, immunology, and metabolism. The completion of these studies will address a central question in the area of type 2 diabetes, fill an important gap in our knowledge, and significantly advance our understanding of how depot-specific functions of WAT are regulated during obesity.
Obesity is a major risk factor for type 2 diabetes, coronary artery disease, and for some cancers and neurodegenerative diseases. In both mice and humans, obesity promotes chronic low-grade inflammation, which contributes to the pathogenesis of these obesity-associated diseases. Studies in this grant application aim to elucidate novel regulatory pathways that contribute to the pathogenesis of obesity-induced inflammation and metabolic disease.
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