The menopausal transition, an unavoidable aging related phenomenon in females, is accompanied by increased abdominal adiposity and the concomitant incidence of adipose-related comorbidities. Although previous research has primarily focused on body fat distribution, we have generated evidence that the cellular composition of adipose tissue (AT) defines the phenotype of each individual depot, determining its overall influence on metabolic health. The premise is that the loss of gonadal hormones alters the cellularity of AT, leading to changes in body fat distribution and worsening metabolic health. We previously discovered a novel lineage of adipocytes in the major white adipose depots of mice and humans generated from bone marrow derived cells of the hematopoietic lineage rather than conventional mesenchymal precursors. In mice, bone marrow-derived adipocytes (BMDAs) were detected in greater numbers in abdominal fat depots and displayed increased inflammatory cytokine but decreased leptin and mitochondrial lipid oxidation gene expression, suggesting a critical role in influencing metabolic health. Furthermore, ovariectomy (OVX) significantly increased BMDA production, which was attenuated by estradiol (E2) replacement. In addition to declines in E2, menopause (or OVX) is also characterized by rising follicle stimulating hormone (FSH) levels. Recent research questions whether the consequences of menopause traditionally attributed to the specific loss of ovarian E2 may instead be resultant to the previously unappreciated rise in FSH. Here we expand on our previous observations to test the central hypothesis that E2 and FSH differentially regulate the production of BMDAs, altering the cellular composition of adipose tissue and resulting in significant changes in metabolic and inflammatory phenotype.
Three specific aims will address this hypothesis:
Aim 1 : Determine whether E2 and/or FSH signaling regulate BMDA production in female mice, Aim 2 (Interaction with Project 2): Test whether targeted depletion of BMDAs in female mice reduces OVX-induced changes in energy adiposity, energy balance, inflammation and metabolic health and Aim 3 (Interaction with Project 1): Test the effects of altered circulating FSH and E2 levels on adipocyte precursor sub-population accumulation in subcutaneous adipose tissue of women. Successful completion of these studies will define the role of E2 and FSH in controlling the production of BMDAs, which may contribute to postmenopausal metabolic pathology. These data have the tremendous potential to highlight BMDA production as a new therapeutic target providing novel strategies for the prevention of menopausal and aging related chronic disease risk.
