Defining the role of an endothelial-adipocyte precursor axis in adipocyte hyperplasia

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Project Summary Obesity, which is defined as the excess accumulation of white adipose tissue (WAT) is associated with the development of numerous metabolic, inflammatory, and cardiovascular derangements. However, it is the accumulation of visceral adipose (VWAT) that is associated with metabolic diseases, while the accumulation of subcutaneous adipose (SWAT) is thought to protect against the development of obesity-associated disease. Sex hormones are known to influence both the accumulation of adipose, adipose distribution between VWAT and subcutaneous adipose (SWAT), and the development of metabolic disease, but the precise mechanisms by which sex hormones influence adipose function and distribution remain unclear. We have previously shown that there is an obesity-specific mechanism of adipogenesis that drives adipocyte hyperplasia in a sex-specific pattern. Estrogen plays a role in this process, where exogenous estrogen drives a female-like patterning (both VWAT and SWAT) of adipocyte hyperplasia in male mice, while the absence of systemic estrogen in female mice results in male-like patterning (VWAT only response). Our preliminary data indicates that in the absence of systemic estrogen, estrogen signaling still plays a direct role in VWAT adipocyte hyperplasia at the onset of obesity. We show here that it is VWAT endothelial cells that express aromatase and thereby produce the estrogen required for adipocyte hyperplasia in males and ovariectomized females. We propose that aromatase expression in VWAT endothelium is controlled by glucocorticoids, linking the VWAT-specific actions of estrogen to the hypothalamic-pituitary-adrenal (HPA) axis. Based on our preliminary data, we hypothesize that estrogen and glucocorticoids participate in an endothelial cell-adipocyte precursor axis that regulates obesogenic adipogenesis, thereby influencing distribution of WAT and impacting metabolic disease. Here we will establish the role of adipose- produced estrogen in obesity and metabolic disease, determine the mechanisms that regulate aromatase in VWAT endothelial cells and define the molecular mechanisms of that regulate estrogen action in adipocyte precursors.