Estrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice

Female protection against cardiometabolic disease wanes after menopause, concomitant with a transition toward the male-like pattern of visceral adiposity. Since recruitment of adipose progenitor cells (APCs) to support adipose expansion is depot-specific and thought to maintain metabolic homeostasis, sex differences in the capacity for APC differentiation were explored as a mechanism underlying female cardiometabolic protection. Female APCs from subcutaneous depots were more proliferative and responsive to adipogenic stimuli and were enriched in pathways regulating cell cycle compared with male APCs. The female bias toward a higher number of committed preadipocytes in subcutaneous depots was reversed by ovariectomy (ovx) and restored in ovx females with 17β-estradiol (E2) replacement. In response to pharmacological stimulation of adipogenesis by rosiglitazone, intact females gained more fat mass and were protected against the diminished abundance of subcutaneous APCs that was observed in males. Ovx eliminated fat accumulation in response to rosiglitazone, but amplified diet-induced obesity and abolished female protection against metabolic dysfunction. E2 replacement restored female protection against obesity-associated adipose inflammation and metabolic dysfunction. Thus, we conclude that E2 mediates hyperplastic expansion in subcutaneous depots and preserves adipose function in premenopausal women. Article Highlights We undertook this study to elucidate the role of adipose progenitor cells (APCs) in governing sex differences in metabolic disease susceptibility and the heightened risk for metabolic disease in women after menopause. How do sex and estrogen influence APC differentiation capacity in subcutaneous adipose depots, and how does this relate to metabolic function in obesity? Estrogen mediates the recruitment of APCs for hyperplastic expansion of subcutaneous depots, which may contribute to female-specific protection against obesity-induced metabolic disease. Our findings highlight an underrecognized contributor to sex differences in the risk for obesity-associated metabolic disease throughout the life course and implore a revision of the adipose tissue expandability hypothesis in consideration of the influence of sex.