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

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

Research output: Contribution to journalArticle

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 wholebody glucose homeostasis, controlled by local hypoxia signaling in the skeleton.

Original languageEnglish (US)
Pages (from-to)1087-1105
Number of pages19
JournalJournal of Clinical Investigation
Volume128
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Dirckx, N., Tower, R. J., Mercken, E. M., Vangoitsenhoven, R., Moreau-Triby, C., Breugelmans, T., Nefyodova, E., Cardoen, R., Mathieu, C., Van Der Schueren, B., Confavreux, C. B., Clemens, T. L., & Maes, C. (2018). Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. Journal of Clinical Investigation, 128(3), 1087-1105. https://doi.org/10.1172/JCI97794