Overactivation of NF-κB impairs insulin sensitivity and mediates palmitate-induced insulin resistance in C2C12 skeletal muscle cells.
Lipid-induced insulin resistance is associated with inflammatory state in epidemiological studies. However, it is still unclear whether the activation of NF-κB, a pivotal transcription factor of inflammation, plays a crucial role in mediating skeletal muscle insulin resistance. This study addressed what was the role of NF-κB in lipid-induced insulin resistance and whether NF-κB activation was sufficient to cause insulin resistance in C2C12 myotubes. A 16 h exposure of myotubes to palmitate reduced net insulin-stimulated glucose uptake by 48%, GLUT4 translocation by 52%, Akt phosphorylation by 54%, induced a 1.8-fold increase in insulin-stimulated insulin receptor substrate (IRS) phosphorylation, and doubled NF-κB activation. Myotubes transfected with NF-κB p65 siRNA for 24 h and followed by a treatment with palmitate for 16 h efficiently blocked NF-κB activation, and prevented the detrimental effects of palmitate on the metabolic actions of insulin. Transfection of myotubes with I-κBα siRNA for 24 h also led to a twofold induction of NF-κB activation, and reduced net insulin-stimulated glucose uptake by 30%, GLUT4 translocation by 35%, Akt phosphorylation by 31%, induced a 0.7-fold increase in insulin-stimulated IRS phosphorylation. These findings suggest that NF-κB overexpression per se is sufficient to impair insulin sensitivity and palmitate-induced insulin resistance is mediated by NF-κB in skeletal muscle cells.
Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China.
Jingwen
J
Zhang
Wen
W
Wu
Dongfeng
D
Li
Ying
Y
Guo
Helin
H
Ding
D000818:Animals; D002460:Cell Line; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D018485:Muscle Fibers, Skeletal; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000633:toxicity*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering
D051275:Glucose Transporter Type 4; D020672:I-kappa B Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D019308:Palmitic Acid; D003847:Deoxyglucose; D051057:Proto-Oncogene Proteins c-akt