Overactivation of NF-κB impairs insulin sensitivity and mediates palmitate-induced insulin resistance in C2C12 skeletal muscle cells

• Published in: Endocrine 2010-02, Vol.37 (1), p.157-166
• Main Authors: Zhang, Jingwen, Wu, Wen, Li, Dongfeng, Guo, Ying, Ding, Helin
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Deoxyglucose - pharmacokinetics; Diabetes; Endocrinology; Gene Expression Regulation; Gene Silencing; Glucose Transporter Type 4 - metabolism; Humanities and Social Sciences; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Inflammation - metabolism; Insulin - metabolism; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Internal Medicine; Medicine; Medicine & Public Health; Mice; multidisciplinary; Muscle Fibers, Skeletal; Myoblasts, Skeletal - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Original Article; Palmitic Acid - toxicity; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering; Science
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-009-9283-y

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.