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.
Bibliographical noteFunding Information:
We thank G. Ren for mouse genotyping, Yung-Yu Huang for HPLC analysis, X. Sherry Liu for MicroCT analysis, Marya Shanabrough for electrophysiological recordings, and Dr. Patricia Ducy for critical reading of the manuscript. Special thanks to Drs. Bradford B. Lowell, Joel K. Elmquist, Streamson Chua Jr., Yong Xu, Harveen Dhillon and J.M. Zigman for generously providing loxTB Htr2c, ObRb floxed, and Sf1-Cre mice. This work was supported by grants from the NIH (G.K.), a Gideon and Sevgi Rodan fellowship from IBMS (V.K.Y.), HFSP (F.O.), FRM (F.O.), foundation Bettencourt Schueller (F.O. and C.C.), and the Philippe foundation (F.O. and C.C.). G.K. is the founder of Escoublac.
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