A serotonin and melanocortin circuit mediates D-fenfluramine anorexia

Yong Xu, Juli E. Jones, Danielle A. Lauzon, Jason G. Anderson, Nina Balthasar, Lora K. Heisler, Andrew R. Zinn, Bradford B. Lowell, Joel K. Elmquist

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT2CRs) significantly attenuated D-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT2CRs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of D-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of D-Fen. Thus, our results identify a neurochemically defined neural circuit through which D-Fen influences appetite and thereby indicate that this 5-HT2CR/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.

Original languageEnglish (US)
Pages (from-to)14630-14634
Number of pages5
JournalJournal of Neuroscience
Volume30
Issue number44
DOIs
StatePublished - Nov 3 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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    Xu, Y., Jones, J. E., Lauzon, D. A., Anderson, J. G., Balthasar, N., Heisler, L. K., Zinn, A. R., Lowell, B. B., & Elmquist, J. K. (2010). A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. Journal of Neuroscience, 30(44), 14630-14634. https://doi.org/10.1523/JNEUROSCI.5412-09.2010