title: A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.
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.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Yadav
authors.forename: Franck
authors.initials: F
authors.lastname: Oury
authors.forename: Nina
authors.initials: N
authors.lastname: Suda
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Gao
authors.forename: Cyrille
authors.initials: C
authors.lastname: Confavreux
authors.forename: Kristen C
authors.initials: KC
authors.lastname: Klemenhagen
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
authors.forename: Jay A
authors.initials: JA
authors.lastname: Gingrich
authors.forename: X Edward
authors.initials: XE
authors.lastname: Guo
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Tecott
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Rene
authors.initials: R
authors.lastname: Hen
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D001066:Appetite; D015519:Bone Density; D001933:Brain Stem / Q000378:metabolism; D004734:Energy Metabolism; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D012701:Serotonin