Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice
Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice
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DOI：
10.1172/jci74726
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发表时间：
2014-10-01
影响因子：
15.9
通讯作者：
Xu, Yong
中科院分区：
文献类型：
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作者：
Cao, Xuehong;Xu, Pingwen;Xu, Yong
暴饮暴食折磨着大约5%的美国成年人，尽管有效的治疗方法有限。在这里，我们发现雌激素替代疗法可以显著抑制切除卵巢的雌性小鼠的暴食行为。雌激素依赖性抑制暴食在雌性小鼠中缝背核（DRN）5-羟色胺（5-HT）神经元中特异性缺乏雌激素受体α（ER α）的情况下被阻断。最近开发的胰高血糖素样肽-1-雌激素（GLP-1-雌激素）结合物的管理，旨在提供雌激素GLP 1受体增强区有效靶向生物活性雌激素的DRN和基本上抑制暴食样卵巢切除雌性小鼠。单独施用GLP-1减少暴食样进食，但程度与GLP-1-雌激素缀合物不同。给小鼠DRN 5-HT神经元施用ER α选择性激动剂丙基吡唑试验（PPT）以ER α依赖性方式激活这些神经元。PPT还抑制小电导Ca 2+激活的K+（SK）电流; SK电流的阻断阻止PPT诱导的DRN 5-HT神经元的激活。此外，在DRN的SK电流的局部抑制显着抑制暴食样雌性小鼠。总之，我们的数据表明，雌激素作用于ER α，抑制DRN 5-HT神经元中的SK电流，从而激活这些神经元，抑制暴食样进食行为，并建议DRN 5-HT神经元中的ER α和/或SK电流作为抗暴食治疗的潜在靶点。
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 (ER alpha) 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 ER alpha-selective agonist propylpyrazole trial (PPT) to murine DRN 5-HT neurons activated these neurons in an ER alpha-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 ER alpha to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ER alpha and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.