Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in female rodents. Here, we ablate estrogen receptor alpha (ERα); in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα; in the arcuate nucleus increases bone mass in both intact and estrogen-depleted females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα; activity in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly identified female brain-to-bone pathway exists as a homeostatic regulator to divert calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for the treatment of age-related bone disease.

Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice