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Palmitate Induces Tumor Necrosis Factor- Expression in C2C12 Skeletal Muscle Cells by a Mechanism Involving Protein Kinase C and Nuclear Factor-B Activation

Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain

Address all correspondence and requests for reprints to: Manuel Vázquez-Carrera Unitat de Farmacologia. Facultat de Farmàcia, Diagonal 643, E-08028 Barcelona, Spain. E-mail: mvazquezcarrera{at}ub.edu.

The mechanisms responsible for increased expression of TNF- in skeletal muscle cells in diabetic states are not well understood. We examined the effects of the saturated acid palmitate on TNF- expression. Exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate enhanced mRNA (25-fold induction, P < 0.001) and protein (2.5-fold induction) expression of the proinflammatory cytokine TNF-. This induction was inversely correlated with a fall in GLUT4 mRNA levels (57% reduction, P < 0.001) and glucose uptake (34% reduction, P < 0.001). PD98059 and U0126, inhibitors of the ERK-MAPK cascade, partially prevented the palmitate-induced TNF- expression. Palmitate increased nuclear factor (NF)-B activation and incubation of the cells with the NF-B inhibitors pyrrolidine dithiocarbamate and parthenolide partially prevented TNF- expression. Incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C (PKC), abolished palmitate-induced TNF- expression, and restored GLUT4 mRNA levels. Palmitate treatment enhanced the expression of phospho-PKC, suggesting that this PKC isoform was involved in the changes reported, and coincubation of palmitate-treated cells with the PKC inhibitor chelerythrine prevented the palmitate-induced reduction in the expression of IB and insulin-stimulated Akt activation. These findings suggest that enhanced TNF- expression and GLUT4 down-regulation caused by palmitate are mediated through the PKC activation, confirming that this enzyme may be a target for either the prevention or the treatment of fatty acid-induced insulin resistance.

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