{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T11:13:39Z","timestamp":1783509219231,"version":"3.55.0"},"reference-count":53,"publisher":"Bioscientifica","issue":"2","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":45,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>Membrane-initiated estrogen receptor-\u03b1 (mER\u03b1) signaling has been demonstrated to be crucial for normal bone metabolism, and our previous work has confirmed its essential role in osteoblasts. However, the contribution of brain-derived mER\u03b1 signaling to bone homeostasis remains unexplored. To investigate the role of brain-derived mER\u03b1 signaling in bone metabolism, we developed a POMC-C451Af\/f mouse model in which mER\u03b1 signaling is selectively inactivated in POMC-expressing neurons. Gonadal-intact female POMC-C451Af\/f mice exhibited disturbed sex steroid levels and significantly increased bone mass in both cortical and trabecular compartments compared to littermate C451Af\/f controls after sexual maturation (16 weeks old). In ovariectomized female POMC-C451Af\/f mice, estradiol (E2) treatment enhanced the anabolic response in trabecular bone of the femur compared to controls, while the estrogen response in cortical bone was similar between the genotypes. Gonadal-intact male POMC-C451Af\/f mice displayed altered levels of testosterone compared to controls at 24 weeks of age. In orchiectomized male mice, responses to E2 treatment were similar across all examined parameters between POMC-C451Af\/f and control mice. In conclusion, our findings reveal an important role of membrane-initiated ER\u03b1 signaling in POMC neurons in regulating hormone balance and bone metabolism, with more pronounced effects in female mice.<\/jats:p>","DOI":"10.1530\/joe-25-0462","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:17:46Z","timestamp":1778775466000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":0,"title":["Membrane-initiated estrogen receptor-\u03b1 signaling in the hypothalamus regulates trabecular bone in femur in female 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