title: Overexpression of glutamine: fructose-6-phosphate amidotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance.
abstract: 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 x mg(-1) x min(-1) in transgenic mice vs. 176 +/- 18 pmol x mg(-1) x 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 pmol/g in transgenic mice vs. 32.8 +/- 1.3 micromol/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 x kg(-1) x min(-1) in transgenic mice vs. 191 +/- 6 mg x kg(-1) x 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.
authors: Department of Medicine, University of Utah School of Medicine, Veterans Administration Medical Center, Salt Lake City 84132, USA.
authors: G
authors: G
authors: Veerababu
authors: J
authors: J
authors: Tang
authors: R T
authors: RT
authors: Hoffman
authors: M C
authors: MC
authors: Daniels
authors: L F
authors: LF
authors: Hebert
authors: E D
authors: ED
authors: Crook
authors: R C
authors: RC
authors: Cooksey
authors: D A
authors: DA
authors: McClain
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005944:Glucosamine / Q000031:analogs & derivatives; D018149:Glucose Intolerance / Q000097:blood / Q000209:etiology*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000209:etiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D009765:Obesity / Q000209:etiology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D006005:Phosphorylases / Q000378:metabolism; D012016:Reference Values; D014280:Triglycerides / Q000097:blood; D014536:Uridine Diphosphate N-Acetylgalactosamine / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D014280:Triglycerides; C026712:UDP-glucosamine; D014536:Uridine Diphosphate N-Acetylgalactosamine; D000255:Adenosine Triphosphate; D006003:Glycogen; D006005:Phosphorylases; D006006:Glycogen Synthase; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005944:Glucosamine