Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects

• Published in: The Journal of biological chemistry Vol. 278; no. 46; pp. 45777 - 45784
• Main Authors: Rotter, Victoria, Nagaev, Ivan, Smith, Ulf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.11.2003
• Subjects: 3T3-L1 Cells; Adipocytes - metabolism; Adipose Tissue - metabolism; Adult; Animals; Biological Transport; Blotting, Northern; Cytokines - metabolism; Dose-Response Relationship, Drug; Glucose - metabolism; glucose transporter GLUT4; Glucose Transporter Type 4; GLUT-4 protein; Humans; Insulin Receptor Substrate Proteins; insulin receptors; Insulin Resistance; insulin-receptor substrate 1 protein; insulin-receptor substrate 2; Interleukin-6 - metabolism; Interleukin-8 - metabolism; IRS-1 protein; JNK Mitogen-Activated Protein Kinases; JNK protein; MAP Kinase Kinase 4; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases - metabolism; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; peroxisome proliferator-activated receptors; Phosphoproteins - metabolism; Phosphorylation; Proteins - metabolism; pS-307 protein; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA - metabolism; RNA, Messenger - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors; Transcription Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha - metabolism; Tyrosine - chemistry; Tyrosine - metabolism; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M301977200

Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. We here show that human subcutaneous adipose cells, like 3T3-L1 cells, are target cells for IL-6. To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor α (TNF-α). IL-6, in contrast to TNF-α, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. However, IL-6, like TNF-α exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor γ. This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. An important interaction with TNF-α was found because TNF-α markedly increased IL-6 mRNA and protein secretion. These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-α, IL-6 does not increase pS-307 (or pS-612) of IRS-1. The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-α and IL-8, was markedly increased (∼15-fold) in human fat cells from insulin-resistant individuals. We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance.