Hinoi Eiichi, Gao Nan, Jung Dae Young, Yadav Vijay, Yoshizawa Tatsuya, Myers Martin G, Chua Streamson C, Kim Jason K, Kaestner Klaus H, Karsenty Gerard
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Cell Biol. 2008 Dec 29;183(7):1235-42. doi: 10.1083/jcb.200809113. Epub 2008 Dec 22.
The osteoblast-secreted molecule osteocalcin favors insulin secretion, but how this function is regulated in vivo by extracellular signals is for now unknown. In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function. Remarkably, for our purpose, an osteoblast-specific ablation of sympathetic signaling results in a leptin-dependent hyperinsulinemia. In osteoblasts, sympathetic tone stimulates expression of Esp, a gene inhibiting the activity of osteocalcin, which is an insulin secretagogue. Accordingly, Esp inactivation doubles hyperinsulinemia and delays glucose intolerance in ob/ob mice, whereas Osteocalcin inactivation halves their hyperinsulinemia. By showing that leptin inhibits insulin secretion by decreasing osteocalcin bioactivity, this study illustrates the importance of the relationship existing between fat and skeleton for the regulation of glucose homeostasis.
成骨细胞分泌的分子骨钙素有利于胰岛素分泌，但目前尚不清楚这种功能在体内是如何由细胞外信号调节的。在本研究中，我们发现，相反抑制胰岛素分泌的瘦素部分利用交感神经系统来实现这一功能。值得注意的是，就我们的研究目的而言，成骨细胞特异性交感信号缺失会导致瘦素依赖性高胰岛素血症。在成骨细胞中，交感神经张力刺激Esp的表达，Esp是一种抑制骨钙素活性的基因，而骨钙素是一种胰岛素促分泌剂。因此，Esp失活使ob/ob小鼠的高胰岛素血症加倍，并延缓葡萄糖不耐受，而骨钙素失活使其高胰岛素血症减半。通过表明瘦素通过降低骨钙素生物活性来抑制胰岛素分泌，本研究阐明了脂肪与骨骼之间的关系对于调节葡萄糖稳态的重要性。
