Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cells

Biochim Biophys Acta. 2005 May 1;1734(1):52-61. doi: 10.1016/j.bbalip.2005.02.002. Epub 2005 Mar 17.

Abstract

The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood, but there is a strong correlation between insulin resistance and intramyocellular lipid accumulation in skeletal muscle. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. The aim of this work was to study whether the exposure of skeletal muscle cells to palmitate affected peroxisome proliferator-activated receptor (PPAR) beta/delta activity. Here, we report that exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate reduced (74%, P<0.01) the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK-4), which is involved in fatty acid utilization. This reduction was not observed in the presence of the PPARbeta/delta agonist L-165041. This drug prevented palmitate-induced nuclear factor (NF)-kappaB activation. Increased NF-kappaB activity after palmitate exposure was associated with enhanced protein-protein interaction between PPARbeta/delta and p65. Interestingly, treatment with the PPARbeta/delta agonist L-165041 completely abolished this interaction. These results indicate that palmitate may reduce fatty acid utilization in skeletal muscle cells by reducing PPARbeta/delta signaling through increased NF-kappaB activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology*
  • Animals
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Insulin Resistance / physiology*
  • Mice
  • Myoblasts, Skeletal / physiology*
  • NF-kappa B / metabolism
  • PPAR delta / agonists*
  • PPAR delta / biosynthesis
  • PPAR-beta / agonists*
  • PPAR-beta / biosynthesis
  • Palmitates / metabolism
  • Palmitates / pharmacology*
  • Palmitic Acid / pharmacology*
  • Phenols / pharmacology*
  • Phenoxyacetates
  • Protein Binding / drug effects
  • Protein Kinases / biosynthesis

Substances

  • 4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid
  • Acetates
  • NF-kappa B
  • PPAR delta
  • PPAR-beta
  • Palmitates
  • Phenols
  • Phenoxyacetates
  • Palmitic Acid
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4