title: Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse.
abstract: OBJECTIVE
  In adipocytes, triacylglycerol synthesis depends on the formation of glycerol 3-phosphate, which originates either from glucose, through glycolysis, or from lactate, through glyceroneogenesis. However, glucose is traditionally viewed as the main precursor of the glycerol backbone and thus, enhanced glucose uptake would be expected to result in increased triacylglycerol synthesis and contribute to obesity.
  
  
  METHODS
  To further explore this issue, we generated a mouse model with chronically increased glucose uptake in adipose tissue by expressing Gck, which encodes the glucokinase enzyme.
  
  
  RESULTS
  Here we show that the production of high levels of glucokinase led to increased adipose tissue glucose uptake and lactate production, improved glucose tolerance and higher whole-body and skeletal muscle insulin sensitivity. There was no parallel increase in glycerol 3-phosphate synthesis in vivo, fat accumulation or obesity. Moreover, at high glucose concentrations, in cultured fat cells overproducing glucokinase, glycerol 3-phosphate synthesis from pyruvate decreased, while glyceroneogenesis increased in fat cells overproducing hexokinase II.
  
  
  CONCLUSIONS
  These findings indicate that the absence of glucokinase inhibition by glucose 6-phosphate probably led to increased glycolysis and blocked glyceroneogenesis in the mouse model. Furthermore, this study suggests that under physiological conditions, when blood glucose increases, glyceroneogenesis may prevail over glycolysis for triacylglycerol formation because of the inhibition of hexokinase II by glucose 6-phosphate. Together these results point to the indirect pathway (glucose to lactate to glycerol 3-phosphate) being key for fat deposition in adipose tissue.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Edifici H, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Muñoz
authors.forename: S
authors.initials: S
authors.lastname: Franckhauser
authors.forename: I
authors.initials: I
authors.lastname: Elias
authors.forename: T
authors.initials: T
authors.lastname: Ferré
authors.forename: A
authors.initials: A
authors.lastname: Hidalgo
authors.forename: A M
authors.initials: AM
authors.lastname: Monteys
authors.forename: M
authors.initials: M
authors.lastname: Molas
authors.forename: S
authors.initials: S
authors.lastname: Cerdán
authors.forename: A
authors.initials: A
authors.lastname: Pujol
authors.forename: J
authors.initials: J
authors.lastname: Ruberte
authors.forename: F
authors.initials: F
authors.lastname: Bosch
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005994:Glycerophosphates / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005994:Glycerophosphates; D007004:Hypoglycemic Agents; D007328:Insulin; D019344:Lactic Acid; C029620:alpha-glycerophosphoric acid; D005941:Glucokinase; D005947:Glucose