TY - JOUR
T1 - Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts
AU - Li, Zhu
AU - Frey, Julie L.
AU - Wong, G. William
AU - Faugere, Marie Claude
AU - Wolfgang, Michael J.
AU - Kim, Jason K.
AU - Riddle, Ryan C.
AU - Clemens, Thomas L.
N1 - Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/11
Y1 - 2016/11
N2 - Recent studies have identified the osteoblast as an insulin responsive cell that participates in global energy homeostasis. Here, we show that glucose transporter-4 (Glut4) is required for insulindependent uptake and oxidation of glucose in mature osteoblasts. In primary cultures of mouse osteoblasts, insulin increased uptake and oxidation of 14C-glucose in a dose-dependent fashion but did not significantly affect uptake or oxidation of 14C-oleate. In vitro, undifferentiated osteoblasts expressed 3 high-Affinity Gluts: Glut1, Glut4, and Glut3. However, although levels of Glut1 and Glut3 remained constant during the course of osteoblast differentiation, Glut4 expression increased by 5-fold in association with enhanced insulin-stimulated glucose uptake. Glut4 ablation in osteoblasts in vitro eliminated insulin-stimulated glucose uptake, reduced proliferation and diminished measures of osteoblast maturation. In vivo, Glut4 expression was observed in osteoblasts, osteocytes, and chondrocytes at a level approaching that observed in adjacent skeletal muscle. To determine the importance of Glut4 in bone in vivo, we generated mice lacking Glut4 in osteoblasts and osteocytes (δGlut4). δGlut4 mice exhibited normal bone architecture but exhibited an increase in peripheral fat in association with hyperinsulinemia, β-cell islet hypertrophy, and reduced insulin sensitivity. Surprisingly, the expression of insulin target genes in liver, muscle, and adipose from δGlut4 mice were unchanged or increased, indicating that alterations in glucose homeostasis were the result of reduced clearance by bone. These findings suggest that Glut4 mediates insulin-stimulated glucose uptake by mature osteoblasts/osteocytes and that the magnitude of glucose use by bone cells is sufficient to impact global glucose disposal in the mouse.
AB - Recent studies have identified the osteoblast as an insulin responsive cell that participates in global energy homeostasis. Here, we show that glucose transporter-4 (Glut4) is required for insulindependent uptake and oxidation of glucose in mature osteoblasts. In primary cultures of mouse osteoblasts, insulin increased uptake and oxidation of 14C-glucose in a dose-dependent fashion but did not significantly affect uptake or oxidation of 14C-oleate. In vitro, undifferentiated osteoblasts expressed 3 high-Affinity Gluts: Glut1, Glut4, and Glut3. However, although levels of Glut1 and Glut3 remained constant during the course of osteoblast differentiation, Glut4 expression increased by 5-fold in association with enhanced insulin-stimulated glucose uptake. Glut4 ablation in osteoblasts in vitro eliminated insulin-stimulated glucose uptake, reduced proliferation and diminished measures of osteoblast maturation. In vivo, Glut4 expression was observed in osteoblasts, osteocytes, and chondrocytes at a level approaching that observed in adjacent skeletal muscle. To determine the importance of Glut4 in bone in vivo, we generated mice lacking Glut4 in osteoblasts and osteocytes (δGlut4). δGlut4 mice exhibited normal bone architecture but exhibited an increase in peripheral fat in association with hyperinsulinemia, β-cell islet hypertrophy, and reduced insulin sensitivity. Surprisingly, the expression of insulin target genes in liver, muscle, and adipose from δGlut4 mice were unchanged or increased, indicating that alterations in glucose homeostasis were the result of reduced clearance by bone. These findings suggest that Glut4 mediates insulin-stimulated glucose uptake by mature osteoblasts/osteocytes and that the magnitude of glucose use by bone cells is sufficient to impact global glucose disposal in the mouse.
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U2 - 10.1210/en.2016-1583
DO - 10.1210/en.2016-1583
M3 - Article
C2 - 27689415
AN - SCOPUS:84994274922
SN - 0013-7227
VL - 157
SP - 4094
EP - 4103
JO - Endocrinology
JF - Endocrinology
IS - 11
ER -