Overexpression of glutamine : fructose-6-phosphate amidotransferase in theliver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance

To examine the effect of increased hexosamine flux in Liver, the rate-limit ing enzyme in hexosamine biosynthesis (glutamine:fructose-6-phosphate amido transferase [GFA]) was overexpressed in transgenic mice using the PEPCK pro moter. Liver from random-fed transgenic mice had 1.6-fold higher GFA activi ty compared with nontransgenic control littermates (276 +/- 24 pmol.mg(-1). min(-1) in transgenic mice vs. 176 +/- 18 pmol.mg(-1).min(-1) in controls, P < 0.05) and higher levels of the hexosamine end product UDP-N-acetyl gluc osamine (288 +/- 11 pmol/g in transgenic mice vs. 233 +/- 10 pmol/g in cont rols, P < 0.001). Younger transgenic mice compared with control mice had lo wer 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). A t 6 months of age, transgenic animals had normal insulin sensitivity by the hyperinsulinemic clamp technique. Hepatic glycogen content was higher in t he 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 activ ation of glycogen synthase. Serum levels of free fatty acids (FFAs) and tri glycerides were also elevated (FFAs, 0.67 +/- 0.03 mmol/l in transgenic mic e vs. 0.14 +/- 0.01 in controls; triglycerides, 1.34 +/- 0.15 mmol/l in tra nsgenic mice vs. 0.38 +/- 0.01 in controls, P < 0.01). Older transgenic mic e became heavier than control mice and exhibited relative glucose intoleran ce and insulin resistance. The glucose disposal rate at 8 months of age was 154 +/- 5 mg.kg(-1) min(-1) in transgenic mice vs. 191 +/- 6 mg.kg-1.min(- 1) in controls (P < 0.05). me conclude that hexosamines are mediators of gl ucose 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.