title: Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes.
abstract: Fatty acids can activate proinflammatory pathways leading to the development of insulin resistance, but the mechanism is undiscovered. Toll like receptor 2 (TLR2) recognizes lipids, activates proinflammatory pathways, and is genetically associated with inflammatory diseases. This study aimed to examine the role of TLR2 in palmitate-induced insulin resistance in C2C12 myotubes. Treatment with palmitate rapidly induced the association of myeloid differentiation factor 88 (MyD88) with the TLR2 receptor, activated the stress-linked kinases p38, JNK, and protein kinase C, induced degradation of IkappaBalpha, and increased NF-kappaB DNA binding. The activation of these pathways by palmitate was sensitive and temporally regulated and occurred within the upper physiologic range of saturated fatty acid concentrations in vivo, suggesting a receptor-mediated event and not simple lipotoxicity. When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. Palmitate inhibited insulin signal transduction in C2C12 cells beginning 1-2 h after exposure and reached a maximum at 12-16 h. An antagonist TLR2 antibody, mAb 2.5, led to a 50-60% decrease in palmitate-induced IL-6 production and partially restored insulin signal transduction, whereas an isotype-matched control antibody had no effect. RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. This study provides strong evidence that TLR2 mediates the initial events of fatty acid-induced insulin resistance in muscle.
authors.affiliation: Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA. sennj@musc.edu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Senn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation; D005347:Fibroblasts / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D019308:Palmitic Acid / Q000737:chemistry* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D051195:Toll-Like Receptor 2; D000072000:NF-KappaB Inhibitor alpha; D019308:Palmitic Acid; D011493:Protein Kinase C