Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice
Xuehong Cao, … , Qingchun Tong, Yong Xu
Xuehong Cao, … , Qingchun Tong, Yong Xu
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4351-4362. https://doi.org/10.1172/JCI74726.
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Research Article Neuroscience

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

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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Figure 3

ERα in 5-HT neurons mediates estrogenic actions to inhibit binge-like eating in female mice.

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ERα in 5-HT neurons mediates estrogenic actions to inhibit binge-like ea...
(A–D) Representative immunohistochemistry for ERα from female WT (A and C) and KO (B and D) mice (after tamoxifen inductions). Scale bars: 100 μm. 3V, third ventricle; ME, median eminence. (E) WT and KO mice received tamoxifen inductions at 8 weeks of age (3 mg/injections, i.p., 24 hours apart). At 24 weeks of age, mice were ovariectomized and implanted with s.c. 17β-estradiol pellets (0.5 μg/d for 60 days; OVXE) or vehicle pellets (OVXV). After a 7-day recovery, mice were subjected to intermittent HFD exposure for 1 week, as described in Methods. At the end of that week, HFD and chow diet were provided to cages at 11:00 am, and 2.5-hour HFD intake was measured. n = 7–10/group. Results are shown as mean ± SEM. ***P < 0.001, between OVXV and OVXE mice in 2-way ANOVA analyses followed by post hoc Bonferroni’s tests. (F) Body weight, fat mass, and lean mass of WT and KO mice measured when binge-like behavior was assessed. n = 16 or 18/group. Results are shown as mean ± SEM. (G) Plasma orexin A measured in WT and KO mice after assessment of binge-like eating behavior. n = 6–7/group. Results are shown as mean ± SEM.