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

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TitleEstrogens stimulate serotonin neurons to inhibit binge-like eating in mice.
Publication TypeJournal Article
Year of Publication2014
AuthorsCao, X, Xu, P, Oyola, MG, Xia, Y, Yan, X, Saito, K, Zou, F, Wang, C, Yang, Y, Hinton, A, Yan, C, Ding, H, Zhu, L, Yu, L, Yang, B, Feng, Y, Clegg, DJ, Khan, S, DiMarchi, R, Mani, SK, Tong, Q, Xu, Y
JournalJ Clin Invest
Volume124
Issue10
Pagination4351-62
Date Published2014 Oct
ISSN1558-8238
KeywordsAnimals, Binge-Eating Disorder, Estrogen Receptor alpha, Estrogens, Feeding Behavior, Female, Glucagon-Like Peptide 1, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Neurons, Raphe Nuclei, Serotonin
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.

DOI10.1172/JCI74726
Alternate JournalJ. Clin. Invest.
PubMed ID25157819
PubMed Central IDPMC4191033
Grant ListT32CA059268 / CA / NCI NIH HHS / United States
R01DK093587 / DK / NIDDK NIH HHS / United States
K12 GM084897 / GM / NIGMS NIH HHS / United States
P30 DK079638-03 / DK / NIDDK NIH HHS / United States
R00 DK085330 / DK / NIDDK NIH HHS / United States
R01 HD062512 / HD / NICHD NIH HHS / United States
T32 CA059268 / CA / NCI NIH HHS / United States
HD62512 / HD / NICHD NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
R25 GM056929 / GM / NIGMS NIH HHS / United States
P30 DK079638 / DK / NIDDK NIH HHS / United States
R01 DK093587 / DK / NIDDK NIH HHS / United States
P30HD024064 / HD / NICHD NIH HHS / United States
R00DK085330 / DK / NIDDK NIH HHS / United States
R01 DK092605 / DK / NIDDK NIH HHS / United States
R01DK092605 / DK / NIDDK NIH HHS / United States