Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cells.
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.
Jové
Mireia
M
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain.
Laguna
Juan C
JC
Vázquez-Carrera
Manuel
M
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D032448:Myoblasts, Skeletal / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000096:biosynthesis; D048068:PPAR-beta / Q000819:agonists* / Q000096:biosynthesis; D010168:Palmitates / Q000378:metabolism / Q000494:pharmacology*; D019308:Palmitic Acid / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D010642:Phenoxyacetates; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000096:biosynthesis
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D000085:Acetates; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; D010168:Palmitates; D010636:Phenols; D010642:Phenoxyacetates; D019308:Palmitic Acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4