Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid.
The hexosamine signaling pathway has been shown to serve a nutrient-sensing function. We have previously shown that overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine-fructose-6-phosphate amidotransferase) in adipose tissue of transgenic mice results in skeletal muscle insulin resistance and altered regulation of leptin and adiponectin. To dissect the pathways by which the hexosamine pathway affects fuel storage and energy homeostasis, we have examined the characteristics of adipocytes from these animals. After 3 mo of age, epididymal fat pads from adult transgenic animals are 42% heavier (P = 0.003) and individual adipocytes are 23% larger in diameter (P < 0.05) than those from littermate wild-type controls. Isolated adipocytes from transgenic mice are insulin resistant, with a 2.5-fold increase in the ED50 for stimulation of 2-deoxy-D-glucose uptake. However, maximal insulin-stimulated glucose uptake is increased in transgenic adipocytes by 39% (P < 0.05). This upregulation of glucose uptake was associated with a 41% increase in the expression of GLUT4 mRNA and a 28% increase in GLUT4 protein in transgenics compared with controls (P < 0.05). GLUT1 mRNA and protein did not significantly differ between fasted control and transgenics. Total lipid synthesis was also increased in epididymal adipocytes from transgenic animals by 206% compared with controls (P < 0.05). Fatty acid oxidation was increased 1.6-fold in the transgenic adipocytes (P < 0.05). We conclude that the hexosamine signaling pathway upregulates fat storage in adipocytes in states of carbohydrate excess, in part by increasing GLUT4 and glucose uptake and by augmenting fatty acid synthesis.
McClain
Donald A
DA
Veterans Affairs Medical Center, Department of Medicine, 30 N. 2030 East, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. donald.mcclain@hsc.utah.edu
Hazel
Mark
M
Parker
Glendon
G
Cooksey
Robert C
RC
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000254:growth & development / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D005947:Glucose / Q000493:pharmacokinetics*; D051275:Glucose Transporter Type 4; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology
D051275:Glucose Transporter Type 4; D006595:Hexosamines; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D005947:Glucose