title: Cyclooxygenase 2 inhibition exacerbates palmitate-induced inflammation and insulin resistance in skeletal muscle cells.
abstract: Palmitate-induced inflammation is involved in the development of insulin resistance in skeletal muscle cells. Here we evaluated the effect of the saturated fatty acid palmitate and the monounsaturated fatty acid oleate on Toll-like receptors (TLR)-2 and -4 and cyclooxygenase 2 (COX-2) expression and examined whether the inhibition of this enzyme modulates fatty acid-induced inflammation. Skeletal muscle cells exposed to palmitate showed enhanced TLR-2 and COX-2 mRNA levels, whereas oleate did not modify their expression. Palmitate-induced expression of these genes was dependent on nuclear factor (NF)-kappaB activation, because expression was reduced in the presence of the NF-kappaB inhibitor parthenolide. Coincubation of palmitate-exposed cells with oleate also prevented the increase in the expression of TLR-2 and COX-2, through a mechanism that may involve activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) by this monounsaturated fatty acid. COX-2 inhibition by NS-398 enhanced IL-6 and TNF-alpha expression and IL-6 protein secretion induced by palmitate. NF-kappaB binding activity and TNF-alpha mRNA levels were enhanced in palmitate-exposed cells in the absence or in the presence of NS-398, whereas coincubation of palmitate-exposed cells with NS-398 and prostaglandin E(2) (PGE(2)) prevented these changes. In contrast, 12-lypoxygenase and cytochrome P450 hydroxylase pathways were not involved in these changes. Similarly, COX-2 inhibition impaired insulin-stimulated Akt phosphorylation and 2-deoxy-D-[(14)C]glucose uptake in palmitate-exposed skeletal muscle cells, and this effect was abolished in the presence of PGE(2). These findings indicate that COX-2 activity, through the production of PGE(2), attenuates the fatty acid-induced inflammatory process and insulin resistance.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry and Institut de Biomedicina de la Universitat de Barcelona, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coll
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Escolà-Gil
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sánchez
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D017931:DNA Primers; D004357:Drug Synergism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005784:Gene Amplification; D007249:Inflammation / Q000139:chemically induced* / Q000503:physiopathology; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019308:Palmitic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D051195:Toll-Like Receptor 2 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D015850:Interleukin-6; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D019308:Palmitic Acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2