title: Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: evidence for PKC activation and oxidative stress-activated signaling pathways.
abstract: In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine(307) phosphorylation of IRS-1. IRS-1 Serine(307) phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IkappaB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKalpha/beta, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms.
authors.affiliation: University of Ain Shams, Department of Biochemistry, Faculty of Science, Cairo 11566, Egypt. rafik.ragheb@utoronto.ca
authors.forename: Rafik
authors.initials: R
authors.lastname: Ragheb
authors.forename: Gamila M L
authors.initials: GM
authors.lastname: Shanab
authors.forename: Amina M
authors.initials: AM
authors.lastname: Medhat
authors.forename: Dina M
authors.initials: DM
authors.lastname: Seoudi
authors.forename: K
authors.initials: K
authors.lastname: Adeli
authors.forename: I G
authors.initials: IG
authors.lastname: Fantus
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013654:Taurine / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D013654:Taurine; D019301:Oleic Acid; D019308:Palmitic Acid; D012694:Serine; D011493:Protein Kinase C; D005947:Glucose
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