LAUSR

Abstract Disclosure: G. Burganova: None. A. Gumerova: None. G. Pevnev: None. Z. Nakadar: None. P.T. Shyu: None. G.F. Guerriero: None. U. Cheliadinova: None. S.L. Sims: None. O. Moldavski: None. O. Barak: None. X.E. Guo: None. D. Lizneva: None. T. Yuen: None. M. Zaidi: None. Obesity is a chronic disease affecting millions of Americans, with postmenopausal women exhibiting higher rates of severe obesity compared to men. Notably, 2-3 years before the cessation of menstruation, follicle-stimulating hormone (FSH) levels rise—independent of estrogen levels—to compensate for declining ovarian reserve. In mouse models of obesity, blockade of FSH has been shown to prevent disease onset. These findings provide a rationale for exploring FSH blockade as a potential therapeutic strategy to reduce adiposity, particularly during perimenopause. To this end, we have developed a lead therapeutic candidate: a humanized monoclonal antibody targeting FSH, termed MS-Hu6, which is currently undergoing preclinical evaluation. This study aims to elucidate the mechanisms through which FSH regulates adiposity, reveal sex-specific differences, and ultimately guide ongoing and future investigations of MS-Hu6. To assess whether FSH acts directly on adipose tissue, we generated a conditional knockout (cKO) mouse model in which the FSH receptor (Fshr) is selectively deleted in adipocytes (Adipoq-Cre;Fshrfl/fl). We fed these mice ad libitum on a high-fat diet, measured their body composition (EchoMRI) and thoracoabdomial white adipose tissue (WAT) compartments (micro-CT), evaluated insulin sensitivity (glucose and insulin tolerance tests), performed tissue histology (immunohistochemistry) and gene expression analyses (real-time PCR). First, we validated the specificity and activity of Adipoq-Cre. Significantly higher Cre expression levels were observed in gonadal WAT in female compared with male Adipoq-Cre+ mice. To confirm Cre activity at the protein level, we crossed Adipoq-Cre mice with R26-EYFP reporter mice (Adipoq-Cre;R26-EYFP) and performed immunohistochemistry using an anti-YFP antibody. Cre-mediated recombination, indicated by YFP expression, was detected in all WAT and brown adipose tissue (BAT) depots. Strikingly, Fshr cKO female mice that inherited the Cre transgene maternally were resistant to weight gain compared to their wild-type littermates. These transgenic females had significantly lower weights and volume of visceral WAT, as confirmed by micro-CT imaging and post-dissection tissue analysis. Additionally, BAT weights in Cre+ transgenic females were lower compared to their Cre- littermates. Furthermore, these mice were protected against glucose intolerance. In contrast, female mice inheriting the Cre transgene paternally, as well as male mice regardless of inheritance pattern, showed no significant phenotype.These results show that FSH acts on adipocyte FSHR, and suppression of FSHR in adipose tissues protects female mice against diet-induced obesity and glucose intolerance. These findings suggest adipose FSHR may constitute a novel therapeutic target for treatment of obesity and metabolic syndrome specifically in females. Presentation: Saturday, July 12, 2025