Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)a. Central ERa exerts an inhibitory role on bone mass. ERa is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERa in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERa expression specifically in POMC neurons (POMC-ERa-/-). Female POMC-ERa-/- and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 µg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERa-/- mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERa in VMN is involved in the regulation of bone mass, ERa was silenced using an adeno-associated viral vector. Silencing of ERa in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERa in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERa activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERa-mediated effects in bone determines cortical bone mass in female mice. Read more »