title: Paraoxonase1 (PON1) reduces insulin resistance in mice fed a high-fat diet, and promotes GLUT4 overexpression in myocytes, via the IRS-1/Akt pathway.
abstract: OBJECTIVE
  To analyze Paraoxonase1 (PON1) impact on GLUT4 expression, glucose metabolism, and the insulin signaling pathway in skeletal muscle cells.
  
  
  RESULTS
  We analyzed the effect of PON1 in high-fat-diet-induced insulin resistance in C57BL/6J and in PON1KO mice. Mice were fed normal diet (ND) or high Fat Diet (HFD) for 8 weeks. PON1 deficiency caused enhanced insulin resistance in both ND and HFD mice. PON1 deficiency was associated with increased oxidative stress (OS), increased p38MAPK activity and attenuated insulin-mediated tyrosine phosphorylation of muscle insulin receptor substrate-1 (IRS-1), with a corresponding increase in serine phosphorylation. These effects resulted in decreased glucose uptake in whole-body level, as reflected by glucose tolerance test (GTT), by insulin tolerance test (ITT) and by cellular glycogen accumulation in the liver and in the muscles. PON1 addition to cultured C2 muscle cells enhanced GLUT4 mRNA expression, in a time and concentration dependent manner, increased GLUT4 protein and cellular glycogen accumulation. These effects were mediated via inhibition of p38MAPK activity, resulting in reduced IRS-1 serine phosphorylation and in enhanced IRS-1 tyrosine phosphorylation. The ability of PON1 to increase myocytes GLUT4 expression was partially inhibited upon blocking PON1 SH group, and completely abolished upon PON1 mutation in HIS115 of its catalytic site.
  
  
  CONCLUSIONS
  PON1 plays a beneficial role in glucose regulation and metabolism and may serve as an important tool in diabetes control.
authors: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa, Israel.
authors: Marie
authors: M
authors: Koren-Gluzer
authors: Michael
authors: M
authors: Aviram
authors: Tony
authors: T
authors: Hayek
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015430:Weight Gain / Q000502:physiology
chemical_list: D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C495693:Slc2a4 protein, mouse; D006003:Glycogen; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse