A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.
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.
Yadav
Vijay K
VK
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Oury
Franck
F
Suda
Nina
N
Liu
Zhong-Wu
ZW
Gao
Xiao-Bing
XB
Confavreux
Cyrille
C
Klemenhagen
Kristen C
KC
Tanaka
Kenji F
KF
Gingrich
Jay A
JA
Guo
X Edward
XE
Tecott
Laurence H
LH
Mann
J John
JJ
Hen
Rene
R
Horvath
Tamas L
TL
Karsenty
Gerard
G
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
D020738:Leptin; D054411:Receptors, Leptin; D012701:Serotonin