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

J Clin Invest. 2014 Oct;124(10):4351-62. doi: 10.1172/JCI74726. Epub 2014 Aug 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binge-Eating Disorder
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor alpha / genetics
  • Estrogens / metabolism*
  • Feeding Behavior / drug effects*
  • Female
  • Glucagon-Like Peptide 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Neurons / metabolism*
  • Raphe Nuclei / metabolism
  • Serotonin / metabolism*


  • Estrogen Receptor alpha
  • Estrogens
  • Serotonin
  • Glucagon-Like Peptide 1