TY - JOUR
T1 - Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism
AU - Dirckx, Naomi
AU - Tower, Robert J.
AU - Mercken, Evi M.
AU - Vangoitsenhoven, Roman
AU - Moreau-Triby, Caroline
AU - Breugelmans, Tom
AU - Nefyodova, Elena
AU - Cardoen, Ruben
AU - Mathieu, Chantal
AU - Van Der Schueren, Bart
AU - Confavreux, Cyrille B.
AU - Clemens, Thomas L.
AU - Maes, Christa
N1 - Funding Information:
The authors thank R. Kroes, B. Dubois, M.C. Carlier, and L. Cham-bard for assistance; A.M. Böhm and M. Mesnieres for help in optimization of techniques; A. Van Santvoort, T. Buelens, C. Casteels, J. Wouters, B. de Laat, and K. Van Laere for sharing small-animal imaging infrastructure and help with tracer assays; and P. Agos-tinis, A. van Vliet, and S. Van Eygen for Seahorse use. We thank A. McMahon and E. Schipani for sharing mouse lines. T.J. Martin, H. Kronenberg, and F. Luyten are acknowledged for critically reading the manuscript and providing valuable input. We also thank F. Giammarile, P. Clézardin, N. Girard, and the members of the SBE for helpful discussions. This work was supported by grants from the European Research Council (ERC Starting Grant 282131 under the European Union’s Seventh Framework Programme, FP/2007–2013), Research Foundation Flanders (FWO, G.094416N), and University of Leuven (OT/14/121) to C. Maes, and by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (subaward to C. Maes of R01AR049410 to TLC). CBC is supported by the Hospices Civils de Lyon (Young Investigator Grant 2011), EMM is an FWO fellow, and ND holds a doctoral fellowship of the Agency for Innovation by Science and Technology in Flanders (IWT).
Publisher Copyright:
© 2018 Blackwell Publishing Ltd. All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI97794
DO - 10.1172/JCI97794
M3 - Article
C2 - 29431735
AN - SCOPUS:85042756875
SN - 0021-9738
VL - 128
SP - 1087
EP - 1105
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
ER -