Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

Authors: CAO, XUEHONG - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - Children'S Nutrition Research Center (CNRC); OYOLA, MARIO - Baylor College Of Medicine; XIA, YAN - Children'S Nutrition Research Center (CNRC); YAN, XIAOFENG - Children'S Nutrition Research Center (CNRC); SAITO, KENJI - Children'S Nutrition Research Center (CNRC); ZOU, FANG - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); HINTON, ANTENTOR - Children'S Nutrition Research Center (CNRC); YAN, CHUNLING - Children'S Nutrition Research Center (CNRC); DING, HONGFANG - Children'S Nutrition Research Center (CNRC); ZHU, LIANGRU - Children'S Nutrition Research Center (CNRC); YU, LIKAI - Children'S Nutrition Research Center (CNRC); YANG, BIN - Indiana University; FENG, YUXIN - University Of Cincinnati; CLEGG, DEBORAH - University Of Texas Southwestern Medical Center; KHAN, SOHAIB - University Of Cincinnati; DIMARCHI, RICHARD - Indiana University; MANI, SHAILA - Baylor College Of Medicine; TONG, QINGCHUN - University Of Texas Health Science Center; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/10/2014
Publication Date: 8/26/2014
Citation: Cao, X., Xu, P., Oyola, M.G., Xia, Y., Yan, X., Saito, K., Zou, F., Wang, C., Yang, Y., Hinton, A., Yan, C., Ding, H., Zhu, L., Yu, L., Yang, B., Feng, Y., Clegg, D.J., Khan, S., Dimarchi, R., Mani, S.K., Tong, Q., Xu, Y. 2014. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. Journal of Clinical Investigation. 124(10):4351-4362.

Interpretive Summary: Binge eating is a serious medical condition, but treatment is limited. Here we showed that the female sex hormone, estrogen, can substantially suppress binge-like eating in female mice. We further demonstrated that estrogen actions are mediated by a specific estrogen receptor expressed by brain serotonin neurons. Finally, we showed that a newly developed estrogenic compound can deliver bioactive estrogen to serotonin neurons in the brain and inhibit binge eating. These findings highlighted estrogen receptors expressed by serotonin neurons as the key regulator of binge eating behavior in females, and it could be a potential target for development of novel therapies for binge eating at least in women.

Technical Abstract: Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-alpha (ERalpha) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate designed to deliver estrogen to GLP1 receptor-enhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1-estrogen conjugate. Administration of ERalpha-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERalpha-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERalpha to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERalpha and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.