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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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 6

Estrogens inhibit SK-like currents in DRN 5-HT neurons.

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Estrogens inhibit SK-like currents in DRN 5-HT neurons. (A) A voltage cl...
(A) A voltage clamp protocol to induce SK-like currents. (B) Representative traces for SK-like currents recorded from a 5-HT neuron before (black) and after (red) apamin perfusion. SK currents were shown as an outward tail current following step depolarization of Vh. (C–E) Representative traces before (black) and after (red) PPT treatment from responsive 5-HT neurons in WT brain slice (C), from 5-HT neurons in KO brain slice (D), from 5-HT neurons in WT slices preincubated with apamin (100 nM, 2 hours) (E). (F) PPT-induced changes in SK-like current in WT responsive neurons, in WT irresponsive neurons, in KO 5-HT neurons, or in WT 5-HT neurons preincubated with apamin (100 nM for 2 hours). n = 7–13/group. Results are shown as mean ± SEM. ***P < 0.001. (G) Effects of intra-DRN preinjections of saline or apamin (50 nM, 0.5 μl) on binge-like eating (2.5-hour HFD intake) in OVXV or OVXE WT and KO female mice. n = 5/group. Results are shown as mean ± SEM. **P < 0.01. (H) Intake of 0.1 M NaCl solution in OVX WT female mice receiving intra-DRN injections of saline or apamin (50 nM, 0.5 μl) in the CTA tests. n = 4/group. Results are shown as mean ± SEM.