The overarching goal of this application is to provide Dr. Gavin the expertise and skills necessary to initiate an independent research career in the field adipose tissue physiology, with a specific focus on defining the role of sex and gonadal hormones in adipocyte development and phenotype. The importance of distinct developmental pathways in adipocyte biology has been largely overlooked because dogma has held that new adipocytes are derived from resident progenitor cells. Recent preclinical advances have revealed that new adipocytes arise from a heterogeneous population of both resident and non-resident progenitor cells. Studies in mice have shown that these non-resident progenitors arise from bone marrow-derived progenitor cells of myeloid lineage (BMP-derived adipocytes). Importantly, we and others have provided evidence of BMP-derived adipocytes in humans. BMP-derived adipocytes appear to have a gene expression pattern that is distinct from white or brown adipocytes. This pattern is characterized by increased inflammatory factors and decreased mitochondrial enzymes, implicating this adipocyte lineage as a potential contributor to the adverse metabolic profile associated with excess adiposity. Preliminary evidence suggests that accumulation of BMP-derived adipocytes is greater in female compared to male mice, and in ovariectomized compared to intact female mice. Furthermore, the accumulation of these cells is increased in visceral depots. Collectively, these studies suggest that gonadal hormone status is mechanistically linked with adipocyte development and the health risks of excess adiposity. Accordingly, the global hypothesis of this project is that gonadal hormones regulate the developmental pathway and metabolic phenotype of new adipocytes in women and men. Specifically, we hypothesize that reduced gonadal steroid hormones favor the recruitment and differentiation of BMP-derived adipocytes. To test these hypotheses, we will obtain subcutaneous abdominal adipose tissue biopsies from women and men before and after gonadal hormone suppression. The stromal fraction will be isolated from adipose tissue and sorted into populations of myeloid and mesenchymal cells by flow cytometry that will then be grown in culture with and without exposure to gonadal hormones.
The Specific Aims are to determine whether 1) gonadal hormone status in women and men alters adipose tissue myeloid cell accumulation and determines their ability to undergo mesenchymal transition in vitro and 2) gonadal hormone status and progenitor lineage (myeloid versus conventional) regulate the proliferation, differentiation, metabolic phenotype, and metabolomics profile of primary human adipocytes. An exploratory aim will be to compare subcutaneous and visceral fat cells obtained from the same individuals undergoing abdominal surgery using the methods proposed in Aims 1 and 2. If successful, our results will provide evidence that some adipocytes in humans can arise from a previously unrecognized origin. Furthermore, it will reveal the importance of gonadal hormone status in determining adipocyte lineage and development.
There is a clear sex difference in the body fat distribution between men and women that is minimized after the menopausal transition, implicating sex hormones as a regulator of body fat. The findings of this research will help us understand how new fat cells are developed, if fat cell development changes with the decline in sex hormones observed in older men and women, and how changes in fat may influence chronic disease risk. The results of this investigation may reveal potential mechanistic targets for future therapies to reduce the negative health outcomes associated with obesity related chronic diseases in a sex specific manner.
