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Palmitate-Induced Interleukin 6 Production Is Mediated by Protein Kinase C and Nuclear-Factor B Activation and Leads to Glucose Transporter 4 Down-Regulation in Skeletal Muscle Cells

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 by which elevated levels of free fatty acids cause insulin resistance are not well understood. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. Here, we report that exposure of C2C12 skeletal muscle cells to 0.5 mM palmitate results in increased mRNA levels (3.5-fold induction; P < 0.05) and secretion (control 375 ± 57 vs. palmitate 1129 ± 177 pg/ml; P < 0.001) of the proinflammatory cytokine IL-6. Palmitate increased nuclear factor-B activation and coincubation of the cells with palmitate and the nuclear factor-B inhibitor pyrrolidine dithiocarbamate prevented both IL-6 expression and secretion. Furthermore, incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C, and phorbol myristate acetate, that down-regulates protein kinase C in long-term incubations, abolished induction of IL-6 production. Finally, exposure of skeletal muscle cells to palmitate caused a fall in the mRNA levels of glucose transporter 4 and insulin-stimulated glucose uptake, whereas in the presence of anti-IL-6 antibody, which neutralizes the biological activity of mouse IL-6 in cell culture, these reductions were prevented. These findings suggest that IL-6 may mediate several of the prodiabetic effects of palmitate.

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