Establishment and Maintenance of Healthy Adipose Tissue in Obesity

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Obesity confers significant risk for developing numerous chronic disorders, such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. Importantly, many obese individuals are relatively resistant to developing these metabolic disorders, at least for a period of time. This implies that factors beyond BMI, per se, drive the development of these conditions. Clinical studies comparing the “metabolically healthy obese” to obese individuals with metabolic syndrome have revealed that the manner by which energy-storing white adipose tissue (WAT) remodels in obesity is a critical determinant of metabolic health. Healthy WAT expansion is characterized by 1) preferential expansion of subcutaneous WAT depots, and 2) adipose tissue expansion through an increase in cell differentiation, or “adipogenesis.” This phenotype correlates well with preserved insulin sensitivity in obesity. Pathologic WAT expansion is characterized by 1) limited expansion of subcutaneous WAT depots, and 2) pathologic WAT remodeling, characterized by limited adipogenesis, adipocyte hypertrophy, inflammation, and fibrosis. These phenotypes correlate with insulin resistance and ectopic lipid accumulation in non-adipose tissues. As such, de novo adipogenesis in the setting of caloric excess is a protective mechanism to ensure safe energy storage in WAT and prevent against the development of metabolic disease. Understanding the mechanisms controlling adipogenesis in anatomically distinct regions in vivo remains a high priority in the field of adipose biology. Adipocyte precursor cells (APCs) reside within the WAT vasculature as a subset of perivascular, PDGFRb+, mural cells. Adipogenesis originating from PDGFRb+ cells in the setting of caloric excess promotes healthy WAT remodeling and insulin sensitivity in mice. Importantly, strong inhibitory signals within the tissue microenvironment control adipogenesis in a region-specific manner. During the next funding cycle, we propose to test the hypothesis that an anti-adipogenic, pro-fibrogenic, HIFa (hypoxia-inducible factor)-dependent signaling cascade suppresses PPARg activity in APCs through serine 112 (S112) phosphorylation to promote unhealthy WAT modeling in obesity. Our specific aims are to 1) determine the role of mural cell HIFa signaling in adipose tissue remodeling in obesity, and 2) identify HIFa-dependent signaling mechanisms leading to the inhibition of PPARg activity and suppression of adipocyte hyperplasia in obesity. Successful completion these aims will advance our understanding of depot-specific adipocyte progenitors and the regulation of adipogenesis in vivo. This may lead to novel therapeutics strategies to uncouple insulin resistance from obesity.