A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Vijay K. Yadav, Franck Oury, Nina Suda, Zhong Wu Liu, Xiao Bing Gao, Cyrille Confavreux, Kristen C. Klemenhagen, Kenji F. Tanaka, Jay A. Gingrich, X. Edward Guo, Laurence H. Tecott, J. John Mann, Rene Hen, Tamas L. Horvath, Gerard Karsenty

Research output: Contribution to journalArticle

424 Citations (Scopus)

Abstract

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Original languageEnglish
Pages (from-to)976-989
Number of pages14
JournalCell
Volume138
Issue number5
DOIs
Publication statusPublished - 2009 Sep 4
Externally publishedYes

Keywords

  • SYSNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yadav, V. K., Oury, F., Suda, N., Liu, Z. W., Gao, X. B., Confavreux, C., Klemenhagen, K. C., Tanaka, K. F., Gingrich, J. A., Guo, X. E., Tecott, L. H., Mann, J. J., Hen, R., Horvath, T. L., & Karsenty, G. (2009). A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure. Cell, 138(5), 976-989. https://doi.org/10.1016/j.cell.2009.06.051