Targeting estrogen receptors to prevent binge eating
Binge eating is associated with obesity and depression. This disorder is more prevalent in women, and there is an apparent correlation between low estrogen levels and this behavior. In this episode, Yong Xu, Xuehong Cao, and Pingwen Xu demonstrate that estrogen replacement therapy attenuates binge eating behaviors in ovariectomized mice and that this effect was mediated by the estrogen receptor-α (ERα) in serotonergic neurons of the dorsal raphe nuclei (DRN). Moreover, systemic delivery of a glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate, which targets estrogen to GLP-1-expressing regions like the DRN, reduced binge eating in ovariectomized females. The results of this study suggest that ERα in the DRN has potential as therapeutic target for treating binge eating–associated disorders.
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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-α (ERα) 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 ERα-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERα-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 ERα to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERα and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.
Authors
Xuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, Yong Xu
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ISSN: 0021-9738 (print), 1558-8238 (online)