Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts.
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 insulin-dependent uptake and oxidation of glucose in mature osteoblasts. In primary cultures of mouse osteoblasts, insulin increased uptake and oxidation of14C-glucose in a dose-dependent fashion but did not significantly affect uptake or oxidation of14C-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.
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Zhu
Z
Li
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Julie L
JL
Frey
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
G William
GW
Wong
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Marie-Claude
MC
Faugere
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Michael J
MJ
Wolfgang
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Jason K
JK
Kim
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Ryan C
RC
Riddle
Department of Orthopaedic Surgery (Z.L., J.L.F., R.C.R., T.L.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology (G.W.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Medicine (M.-C.F.), Division of Nephology, University of Kentucky, Lexington, Kentucky 40356; Department of Biological Chemistry (M.J.W.), Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Wooster, Massachusetts 01605; and Baltimore Veterans Administration Medical Center (R.C.R., T.L.C.), Baltimore, Maryland 21201.
Thomas L
TL
Clemens
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects
D051275:Glucose Transporter Type 4; D007328:Insulin; D005947:Glucose
Cell. 2015 Jun 18;161(7):1576-91
26091038
J Adolesc Health Care. 1985 Nov;6(6):453-5
4055466
Mol Cell. 1998 Nov;2(5):559-69
9844629
Bone. 2012 Feb;50(2):568-75
21550430
Methods Mol Biol. 2009;560:221-38
19504253
J Ultrastruct Res. 1971 Sep;36(5):565-86
4106811
Calcif Tissue Int. 1983 Jul;35(4-5):578-85
6193851
Osteoporos Int. 2005 Dec;16(12):1955-62
16027954
J Anat. 1952 Jul;86(3):259-77
12980877
Cell. 2007 Aug 10;130(3):456-69
17693256
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E327-36
17616608
J Clin Invest. 1999 Dec;104(12):1703-14
10606624
FEBS Lett. 1982 Nov 1;148(1):31-4
6293873
J Clin Invest. 2001 Jul;108(1):153-60
11435467
J Biol Chem. 2012 Mar 23;287(13):10301-15
22275362
Cell. 2000 Jan 21;100(2):197-207
10660043
Bone Res. 2016 Apr 05;4:16004
27088042
Bone. 2008 Aug;43(2):230-7
18538644
Matrix Biol. 2000 May;19(2):85-9
10842091
J Biol Chem. 2002 Nov 15;277(46):44005-12
12215457
Horm Metab Res. 2007 Oct;39(10):717-21
17952832
Mol Cell Biol. 2006 Oct;26(20):7747-59
16908541
J Bone Miner Res. 1988 Aug;3(4):431-8
3223357
J Bone Miner Res. 2010 Jul;25(7):1468-86
20533309
Diabetes. 2011 Mar;60(3):700-9
21266328
J Bone Miner Res. 2011 Sep;26(9):2012-25
21557308
Am J Physiol. 1978 Jan;234(1):C51-5
23680
J Biol Chem. 1960 Apr;235:1206-10
13802861
Cell. 2010 Jul 23;142(2):296-308
20655470
J Clin Invest. 2005 Feb;115(2):291-301
15690082
Cell. 2010 Jul 23;142(2):309-19
20655471
J Biol Chem. 1960 Apr;235:1211-4
13802862
J Cell Biol. 2008 Dec 29;183(7):1235-42
19103808
Mol Cell Biol. 2013 May;33(9):1869-82
23459938