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1 Biochemistry and Molecular Biology, School of Pharmacy, University of Barceona, Barcelona, Barcelona, Spain; Diagonal 643, Barcelona, 08028, Spain
2 Biochemistry and Molecular biology, School of Pharmacy, University of Barcelona, Barcelona, Barcelona, Spain
3 Biochemistry and Molecular Biology, School of Pharmacy, University of Barceona, Barcelona, Barcelona, Spain
* To whom correspondence should be addressed. E-mail: fgarciaheg{at}ub.edu.
Oversupply of lipids to skeletal muscle causes insulin resistance by promoting the accumulation of lipid-derived metabolites that inhibit insulin signaling. In this study we tested the hypothesis that overexpression of carnitine palmitoyltransferase I (CPT I) could protect myotubes from fatty acid-induced insulin resistance by reducing lipid accumulation in the muscle cell. Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides, diacylgycerol and ceramide, produced an activation of PKC 
and PKC 
and blocked insulin-stimulated glucose metabolism, reducing insulin-stimulated PKB activity by 60%. Transduction of L6E9 myotubes with adenoviruses encoding for liver CPT I (LCPT I) wt, or a mutant form of LCPT I (LCPT I M593S), which is insensitive to malonyl-CoA, produced a 2-fold increase in palmitate oxidation when LCPT I activity was increased 3-fold. L-CPT I wt and L-CPT I M593S-overexpressing L6E9 myotubes showed normal insulin-stimulated glucose metabolism and an improvement in PKB activity when pretreated with palmitate. Moreover, LCPT I wt and LCPT I M593S-transduced L6E9 myotubes were protected against the palmitate-induced accumulation of diacylglycerol and ceramide, and PKC and activation. These results suggest that LCPT I overexpression protects L6E9 myotubes from fatty acid-induced insulin resistance by inhibiting both the accumulation of lipid metabolites and the activation of PKC and PKC .
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