Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism
Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism
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DOI：
10.1172/jci97794
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发表时间：
2018-03-01
影响因子：
15.9
通讯作者：
Maes, Christa
中科院分区：
文献类型：
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作者：
Dirckx, Naomi;Tower, Robert J.;Maes, Christa
骨骼已经成为全身葡萄糖稳态的重要调节器，骨钙素和胰岛素代表骨和能量代谢之间相互作用的主要介质。然而，遗传学证据表明，成骨细胞可以影响全球能源代谢，通过额外的，迄今未知的机制。在这里，我们报告说，组成或出生后诱导的缺氧信号通路组件冯希佩尔-林道（VHL）的小鼠骨骼成骨细胞的删除导致高骨量以及低血糖和葡萄糖耐量增加，骨钙素或胰岛素不占。体外和体内数据表明，Vhl缺陷型成骨细胞显示出与HIF-靶基因表达上调相关的大量增加的葡萄糖摄取和糖酵解，类似于典型癌细胞的瓦尔堡效应。总体而言，在突变小鼠中骨骼的葡萄糖消耗增加，如F-18-FDG放射性示踪实验所揭示的。此外，Vhl水平与骨骼葡萄糖摄取水平呈负相关，并且用糖酵解抑制剂二氯乙酸盐（DCA）的药理学治疗（其在体外恢复Vhl缺陷型成骨细胞中的葡萄糖代谢）阻止了突变小鼠中全身代谢表型的发展。总之，这些发现揭示了成骨细胞的细胞葡萄糖代谢和全身葡萄糖稳态之间的新联系，由骨骼中的局部缺氧信号控制。
The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by F-18-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton.