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To examine the effect of increased hexosamine flux in liver, the rate-limiting enzyme in hexosamine biosynthesis (glutamine:fructose-6-phosphate amidotransferase [GFA]) was overexpressed in transgenic mice using the PEPCK promoter. Liver from random-fed transgenic mice had 1.6-fold higher GFA activity compared with nontransgenic control littermates (276 /- 24 pmol [middle dot] mg-1 [middle dot] min-1 in transgenic mice vs. 176 /- 18 pmol [middle dot] mg-1 [middle dot] min-1 in controls, P < 0.05) and higher levels of the hexosamine end product UDP-N-acetyl glucosamine (288 /- 11 pmol/g in transgenic mice vs. 233 /- 10 pmol/g in controls, P < 0.001). Younger transgenic mice compared with control mice had lower fasting serum glucose (4.8 /- 0.5 mmol/l in transgenic mice vs. 6.5 /- 0.8 mmol/l in controls, P < 0.05) without higher insulin levels (48.0 /- 7.8 pmol/l in transgenic mice vs. 56.4 /- 5.4 pmol/l in controls, P = NS); insulin levels were significantly lower in transgenic males (P < 0.05). At 6 months of age, transgenic animals had normal insulin sensitivity by the hyperinsulinemic clamp technique. Hepatic glycogen content was higher in the transgenic mice (108.6 /- 5.2 [mu]mol/g in transgenic mice vs. 32.8 /- 1.3 [mu]mol/g in controls, P < 0.01), associated with an inappropriate activation of glycogen synthase. Serum levels of free fatty acids (FFAs) and triglycerides were also elevated (FFAs, 0.67 /- 0.03 mmol/l in transgenic mice vs. 0.14 /- 0.01 in controls; triglycerides, 1.34 /- 0.15 mmol/l in transgenic mice vs. 0.38 /- 0.01 in controls, P < 0.01). Older transgenic mice became heavier than control mice and exhibited relative glucose intolerance and insulin resistance. The glucose disposal rate at 8 months of age was 154 /- 5 mg [middle dot] kg-1 [middle dot] min-1 in transgenic mice vs. 191 /- 6 mg [middle dot] kg-1 [middle dot] min-1 in controls (P < 0.05). We conclude that hexosamines are mediators of glucose sensing for the regulation of hepatic glycogen and lipid metabolism. Increased hexosamine flux in the liver signals a shift toward fuel storage, resulting ultimately in obesity and insulin resistance.

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