Membrane-initiated Estrogen Receptor-α Signaling in the Hypothalamus Regulates Trabecular Bone in Femur in Female Mice

Membrane-initiated estrogen receptor α (mERα) 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 mERα signaling to bone homeostasis remains unexplored. To investigate the role of brain-derived mERα signaling in bone metabolism, we developed a POMC-C451A f/f mouse model in which mERα signaling is selectively inactivated in POMC-expressing neurons. Gonadal-intact female POMC-C451A f/f mice exhibited disturbed sex steroid levels and significantly increased bone mass in both cortical and trabecular compartments compared to littermate C451A f/f controls after sexual maturation (16 weeks old). In ovariectomized female POMC-C451A f/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-C451A f/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-C451A f/f and control mice. In conclusion, our findings reveal an important role of membrane-initiated ERα signaling in POMC neurons in regulating hormone balance and bone metabolism, with more pronounced effects in female mice.