Location: Children's Nutrition Research CenterTitle: Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction Author
Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/2/2011
Publication Date: 10/5/2011
Citation: Xu, Y., Nedungadi, T.P., Zhu, L., Sobhani, N., Irani, B.G., Davis, K.E., Zhang, X., Zou, F., Gent, L.M., Hahner, L.D., Khan, S.A., Elias, C.F., Elmquist, J.K., Clegg, D.J. 2011. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism. 14(4):453-465. Interpretive Summary: Estrogens are known to prevent body weight gain, but application of estrogen replacement therapy has been hampered due to its side effects, e.g., breast cancers. We showed that estrogens specifically act on two brain cell populations to inhibit eating and to stimulate energy expenditure. These findings indicate that estrogen-responsive cells in the brain are rational targets for anti-obesity therapies especially in post-menopausal women.
Technical Abstract: Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-a(ERa). However, ERalpha-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERalapha 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 ERa in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERalapha in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERalapha from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ERalapha in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERalapha inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERalapha neurons to regulate different aspects of energy homeostasis and reproduction.