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 ¹⁸F-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.

中文翻译：

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成骨细胞中Vhl的缺失促进细胞糖酵解并改善整体葡萄糖代谢

骨骼已成为全身葡萄糖稳态的重要调节剂，骨钙素和胰岛素代表骨骼与能量代谢之间相互作用的主要介质。然而，遗传证据表明，成骨细胞可以通过其他机制（尚不为人所知）影响全球能量代谢。在这里，我们报道小鼠骨骼肌骨浆细胞中缺氧信号通路成分von Hippel–Lindau（VHL）的组成性或出生后诱导的缺失导致高骨量以及低血糖症和糖耐量增加，这不是骨钙素或胰岛素引起的。体外和体内数据表明，Vhl缺陷的成骨细胞显示出与上调的HIF靶基因表达相关的大量葡萄糖摄取和糖酵解，类似于代表癌细胞的Warburg效应。总体而言，如¹⁸ F-FDG放射性示踪剂实验所揭示，在突变小鼠中骨骼消耗的葡萄糖增加了。此外，血糖水平与骨骼葡萄糖的摄取水平呈负相关，而糖酵解抑制剂二氯乙酸盐（DCA）的药理作用可恢复Vhl中的葡萄糖代谢体外缺乏成骨细胞，阻止了突变小鼠体内全身代谢表型的发展。总而言之，这些发现揭示了成骨细胞中的细胞葡萄糖代谢与全身葡萄糖体内稳态之间的新型联系，后者受骨骼中局部缺氧信号的控制。