Distinct Hypothalamic Neurons Mediate Estrogenic Effects on Energy Homeostasis and Reproduction

Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-alpha (ER alpha). However, ER alpha-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ER alpha in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ER alpha in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ER alpha in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ER alpha from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ER alpha in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ER alpha inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ER alpha neurons to regulate different aspects of energy homeostasis and reproduction.