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 Article has an altmetric score of 48

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 3

Osteoprogenitor-targeted Vhl cKO mice are lean, despite normal food intake and reduced physical activity, and display a hypoglycemic phenotype with increased systemic glucose tolerance.

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Osteoprogenitor-targeted Vhl cKO mice are lean, despite normal food inta...
(A) BW of control and constitutive Vhl cKO mice at the indicated ages (n = 3–10/group). (B) Abdominal fat mass as absolute values, in grams (left), and relative as percentage of BW (right) (n = 10–14) in 12-week-old male mice. (C) Representative H&E-stained skin sections. Scale bar: 100 μm. Arrows point to subcutaneous fat. (D) Food intake over 2 days/nights, in absolute values (left) and corrected for the metabolic BW (BW0.75, BW raised to the three-quarter power, as commonly used to normalize energy metabolism data) (right) (n = 6–7). (E) Indirect calorimetry measurements of oxygen consumption, heat production, and ambulatory activity, corrected for BW0.75 (n = 6–7). (F) RER (n = 6–7). (G) Blood glucose levels in random-fed state from P1.5 to P42 (n = 6–8/group). (H) Blood glucose levels after overnight fasting at 12 weeks (n = 7–9). (I) GTT and its quantification as AUC (n = 7–9). (J) Pepck mRNA levels in liver and muscle (n = 4). (K) PAS staining on liver, revealing glycogen content (n = 4). Scale bar: 100 μm. (L) Serum insulin levels in random-fed (left) and fasted (right) conditions (n = 4–9). (M) GSIS (n = 9). conc, concentration. (N) ITT and AUC quantification (n = 6–9). (O) HOMA-IR (n = 9). All analyses were performed on male control and constitutive Vhl cKO mice at 12 weeks of age, unless indicated otherwise. Graphs represent mean ± SEM, and *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test between genotypes, unless indicated otherwise.