Central and peripheral estrogen signaling act in concert to balance skeletal homeostasis. New findings from our research group established that estrogen signaling through Estrogen Receptor Alpha (ERa) in the arcuate nucleus (ARC) of the hypothalamus is a major gatekeeper that distributes energetic resources for reproduction and bone metabolism. ERa signaling in ARC Kisspeptin, Neurokinin-B, Dynorphin (KnDy) expressing neurons opposes the action of peripheral estrogen on bone mass by inhibiting bone formation in female mice. Using three distinct mouse models, genetic ablation of ERa in Kiss1/KnDy neurons elevated trabecular bone mass to 700% (~ 80% BV/TV) in female, but not male mice. This sex-dependent high bone phenotype is accompanied by a large expansion and commitment of adult skeletal stem cells (SSCs) to the bone and cartilage lineages without affecting mesenchymal stem cells (MSCs). To identify the mechanism underlying sex-dependent changes in bone mass and cellular changes in (CD45-; TER119-; Tie2-; AlphaV+; Thy1-; C63-; CD105-; CD200-) SSCs, we used two independent approaches to establish the existence of a circulating brain-dependent osteogenic factor (BDOF) which stimulates new bone formation. We first utilized a parabiont mouse model and paired control wildtype and mutant (Esr1Nkx2-1Cre) females: followed changes in bone volume in the distal femur by in vivo ?CT imaging over a 9 wk period. The density in long bones of control females increased dramatically after being surgically joined to mutants beginning as early as 3 wks. In contrast, bone density actually decreased in control parabionts. SSCs isolated from control femurs joined to mutants also showed an enhanced capacity for osteo- and chondrogenesis in culture. In our second experiment we used an in vivo transplant model. We implanted control bones into control or mutant females, and we observed a large increase in BV/TV after transplanting control distal femurs into 8 wk old mutant females with no changes observed in controls. Kidney capsules transplant studies of isolated control female SSCs into mutant females confirmed the existence of an osteogenic circulatory factor present in mutant female mice. Collectively, our data support the existence of a potent female-specific brain-dependent anabolic bone factor that targets SSCs to expand and form bone. Ongoing efforts are underway to molecularly identify BDOF and then determine if this factor can bone mass in mouse models of osteoporosis in both sexes.