Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor kappaB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells.
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-kappaB activation and coincubation of the cells with palmitate and the nuclear factor-kappaB 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.
Jové
Mireia
M
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, University of Barcelona, E-08028 Barcelona, Spain.
Planavila
Anna
A
Laguna
Juan Carlos
JC
Vázquez-Carrera
Manuel
M
D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051275:Glucose Transporter Type 4; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D010168:Palmitates / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D002518:Ceramides; D051275:Glucose Transporter Type 4; D015850:Interleukin-6; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D010168:Palmitates; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases