Yadav Vijay K, Oury Franck, Suda Nina, Liu Zhong-Wu, Gao Xiao-Bing, Confavreux Cyrille, Klemenhagen Kristen C, Tanaka Kenji F, Gingrich Jay A, Guo X Edward, Tecott Laurence H, Mann J John, Hen Rene, Horvath Tamas L, Karsenty Gerard
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Cell. 2009 Sep 4;138(5):976-89. doi: 10.1016/j.cell.2009.06.051.
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.
瘦素对骨量积累的抑制作用需要特定下丘脑神经元的完整性，但并不依赖于这些神经元上瘦素受体的表达。其对食欲和能量消耗的调节也是如此。这表明瘦素在大脑的其他部位发挥作用以实现这三种功能。我们在此表明，脑干衍生的血清素（BDS）在与腹内侧下丘脑神经元上的Htr2c受体结合后有利于骨量积累，并通过与弓状核神经元上的Htr1a和2b受体结合来调节食欲。瘦素抑制这些功能并增加能量消耗，因为它减少了血清素的合成以及血清素能神经元的放电。因此，虽然消除BDS合成可纠正由瘦素缺乏引起的骨、食欲和能量消耗表型，但血清素能神经元中瘦素受体的失活会完全重现这些表型。这项研究修改了大脑中瘦素信号传导的图谱，并确定了骨代谢和能量代谢共同调节的分子基础。有关本文的视频摘要，请参阅在线提供的补充数据中的PaperFlick文件。
