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

Endocrinology. 2005 Jul;146(7):3087-95. doi: 10.1210/en.2004-1560. Epub 2005 Mar 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Ceramides / pharmacology
  • Down-Regulation*
  • Enzyme Activation / physiology
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Glucose Transporter Type 4
  • Interleukin-6 / biosynthesis*
  • Interleukin-6 / genetics
  • Mice
  • Mitogen-Activated Protein Kinases / physiology
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • NF-kappa B / physiology*
  • Palmitates / pharmacology*
  • Protein Kinase C / metabolism*
  • RNA, Messenger / metabolism


  • Ceramides
  • Glucose Transporter Type 4
  • Interleukin-6
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • NF-kappa B
  • Palmitates
  • RNA, Messenger
  • Slc2a4 protein, mouse
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases