Kim Jae Geun, Sun Ben-Hua, Dietrich Marcelo O, Koch Marco, Yao Gang-Qing, Diano Sabrina, Insogna Karl, Horvath Tamas L
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 406-772, Republic of Korea.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Rep. 2015 Oct 6;13(1):8-14. doi: 10.1016/j.celrep.2015.08.070. Epub 2015 Sep 24.
The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1(-/-) mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.
下丘脑与骨骼代谢有关。弓状核中促进饥饿的神经元是否影响骨骼尚不清楚。我们培育了多品系小鼠以影响AgRP神经元回路的完整性。我们发现，Ucp2基因缺失且AgRP神经元功能受损的小鼠出现了骨质减少。通过在AgRP神经元中细胞选择性重新激活Ucp2，这种表型得到了挽救。当通过出生后早期缺失AgRP神经元或通过细胞自主缺失Sirt1（AgRP-Sirt1(-/-)）损害AgRP神经回路时，小鼠也出现了骨量减少。未发现AgRP神经元中瘦素受体缺失对骨稳态有影响。抑制AgRP-Sirt1(-/-)小鼠的交感神经张力可逆转转基因动物的骨质减少。综上所述，这些观察结果确立了AgRP神经元在骨骼代谢中独立于瘦素作用的重要调节作用。
