Menopause is associated with bone loss and enhanced visceral adiposity. We have shown previously that a polyclonal antibody (Ab) to the β-subunit of the pituitary hormone Fsh increases bone mass in mice. Here, we report that this Ab sharply reduces adipose tissue in wild type mice, phenocopying genetic Fshr haploinsufficiency. The Ab also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue, and enhances thermogenesis. These actions result from the specific binding of Ab to Fshβ to block its action. Our studies uncover novel opportunities for co-treating obesity and osteoporosis.

35Menopause is associated with bone loss and visceral adiposity. Although 36 estrogen prevents bone loss, its inhibitory effect on body fat is less consistent. We 37 questioned instead whether we could target a rising Fsh level during the 38 perimenopausal transition with a single agent to increase bone mass and reduce body 39 fat. We previously showed that a polyclonal antibody (Ab) that binds to the β-subunit of 40Fsh and blocks its interaction with the Fsh receptor (Fshr) increases bone mass. Here, 41we report that the Fsh Ab causes a marked reduction in visceral white adipose tissue 42 (WAT) in mice fed a high fat diet, in ovariectomized mice, and interestingly, in mice on 43 normal chow. The global reduction in body fat, not seen in Fshr -/mice that were 44 similarly treated with Ab, was associated with profound beiging and brown adipose 45 tissue (BAT) activation, noted most impressively in the ThermoMouse, in which Luc2 is 46 driven by an Ucp1 promoter. These changes were accompanied by increased indices 47