SAT667 Follicle-Stimulating Hormone Does Not Directly Regulate Adipogenesis Via The FSH Receptor In Mice

Abstract

Abstract Disclosure: M. Loka: None. L. Ongaro Gambino: None. T. Uliasz: None. L.A. Jaffe: None. L. Kazak: None. D.J. Bernard: None. Rising rates of obesity are a serious public health challenge. Post-menopausal women are at higher risk of developing obesity and associated comorbidities than premenopausal women, with hormonal changes, such as reduced estrogens, likely to be contributing factors. Menopause is also characterized by increases in pituitary-derived follicle-stimulating hormone (FSH). Recent data suggest that FSH may directly stimulate adipogenesis and block thermogenesis in adipocytes. FSH reportedly decreased expression of thermogenic genes (Cox8b and Ucp1) in murine 3T3-L1 cells differentiated into adipocytes. FSH’s inhibitory effects were no longer apparent in the presence of an FSH-neutralizing antibody. The same FSH antibody reduced fat mass and increased lean mass in ovariectomized (OVX) female mice, a rodent model of menopause. In these studies, it was not established whether FSH acted directly through its canonical receptor (FSHR) in adipocytes to mediate its effects. To address this gap, we differentiated 3T3-L1 cells to adipocytes and treated with FSH. In contrast to the earlier report, FSH did not alter the expression of markers of lipogenesis (Cebpa and Pparg2) or thermogenesis (Cox8b and Ucp1) nor did it impact mitochondrial respiration or lipid accumulation. We also did not detect Fshr mRNA in these cells. We next differentiated the stromal vascular fraction from inguinal adipose tissue of adult male mice into white adipocytes. After 10 days of differentiation, FSH treatment did not alter expression of several markers of adipogenesis and did not affect lipid accumulation. To assess FSH actions in vivo, we generated adipocyte-specific Fshr knockout mice (Fshrfx/fx;Adipoq-Cre, hereafter cKO). Ten-week-old cKO and control female mice were OVX and maintained on standard chow. Eight to 10 weeks later, we performed glucose tolerance and insulin tolerance tests, and determined body composition by EchoMRI. Cre-mediated recombination of the floxed Fshr locus in adipocytes was successful, but did not alter body weight, fat or lean mass, or glucose metabolism in cKO relative to control OVX mice. Furthermore, using a newly developed FSHR-3xHA knockin mouse model, we detected FSHR protein expression in ovary, but not in inguinal and perigonadal white adipose depots or in intrascapular brown adipose tissue. We similarly failed to detect Fshr mRNA in various fat depots in control mice. Collectively, our results fail to show FSH effects on adipogenesis in vitro and challenge the hypothesis that FSH acts through the classical FSHR in adipocytes in vivo. Presentation: Saturday, June 17, 2023