Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B.
Recent studies have implicated inhibitor of kappaB kinase (IKK) in mediating fatty acid (FA)-induced insulin resistance. How IKK causes these effects is unknown. The present study addressed the role of nuclear factor kappaB (NFkappaB), the distal target of IKK activity, in FA-induced insulin resistance in L6 myotubes, an in vitro skeletal muscle model. A 6-h exposure of myotubes to the saturated FA palmitate reduced insulin-stimulated glucose uptake by approximately 30%, phosphatidylinositol-3 kinase and protein kinase B phosphorylation by approximately 40%, and stimulated inhibitor of kappaBalpha degradation and the nuclear translocation of NFkappaB. On the other hand, the Omega-3 polyunsaturated FA linolenate neither induced insulin resistance nor promoted nuclear localization of NFkappaB. Supporting the hypothesis that IKK acts through NFkappaB to cause insulin resistance, the IKK inhibitors acetylsalicylate and parthenolide prevented FA-induced reductions in insulin-stimulated glucose uptake and NFkappaB nuclear translocation. Most importantly, NFkappaB SN50, a cell-permeable peptide that inhibits NFkappaB nuclear translocation downstream of IKK, was sufficient to prevent palmitate-induced reductions in insulin-stimulated glucose uptake. Acetylsalicylate, but not NFkappaB SN50, prevented FA effects on phosphatidylinositol-3 kinase activity and protein kinase B phosphorylation. We conclude that FAs induce insulin resistance and activates NFkappaB in L6 cells. Furthermore, inhibition of NFkappaB activation, indirectly by preventing IKK activation or directly by inhibiting NFkappaB nuclear translocation, prevents the detrimental effects of palmitate on the metabolic actions of insulin in L6 myotubes.
Sinha
Sandeep
S
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Perdomo
German
G
Brown
Nicholas F
NF
O'Doherty
Robert M
RM
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D018485:Muscle Fibers, Skeletal / Q000166:cytology*; D018482:Muscle, Skeletal / Q000166:cytology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D035602:Transcriptional Elongation Factors
D002352:Carrier Proteins; D005227:Fatty Acids; D005947:Glucose; D016328:NF-kappa B; D019308:Palmitic Acid; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D035602:Transcriptional Elongation Factors; C114720:Elp1 protein, human