Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism
Naomi Dirckx, … , Thomas L. Clemens, Christa Maes
Naomi Dirckx, … , Thomas L. Clemens, Christa Maes
Published February 12, 2018
Citation Information: J Clin Invest. 2018;128(3):1087-1105. https://doi.org/10.1172/JCI97794.
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Research Article Bone biology

Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

Abstract

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.

Authors

Naomi Dirckx, Robert J. Tower, Evi M. Mercken, Roman Vangoitsenhoven, Caroline Moreau-Triby, Tom Breugelmans, Elena Nefyodova, Ruben Cardoen, Chantal Mathieu, Bart Van der Schueren, Cyrille B. Confavreux, Thomas L. Clemens, Christa Maes

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Figure 11

Schematic summary.

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Schematic summary. Left: Vhl inactivation in osteoprogenitors and the os...
Left: Vhl inactivation in osteoprogenitors and the osteoblast lineage cells derived from them locally leads to excessive HIF stabilization and transcriptional activity, including strong upregulation of glucose transporters (Glut1) and glycolysis-promoting enzymes (Pgk1, Pdk1). These molecular changes are associated with increased glucose uptake and glycolysis in the Vhl-deficient osteolineage cells, and increased glucose consumption by the skeleton as a whole. Right: Systemically, Vhl cKO mice showed consistently reduced blood glucose levels and an increased glucose tolerance that could not be explained through effects on insulin or osteocalcin. Link between local and systemic phenotypes: Since systemic administration of the glycolysis inhibitor DCA rescued the metabolic phenotype, it is possible that the low glycemia was a direct consequence of the increased uptake of glucose in bone, although potential contributions by unknown endocrine-acting osteokines (osteocrine signals) cannot at present be excluded. These new findings strongly suggest that local glucose utilization in the skeleton contributes to systemic glucose clearance and metabolic homeostasis, a concept that may help in the development of therapies beneficial for both bone and metabolic health.