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*

By V. Rotter, I. Nagaev, U. Smith. Journal of Biological Chemistry, 2003

1,127 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/be05dad11c1e0a60bdeab0dfc8e363fa766987a1

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Citations in the corpus

Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB (2005, neutral): “We isolated IKK complexes from mouse liver lysates using anti-IKK-γ antibodies (PharMingen) coupled to protein A-Sepharose, and conducted in vitro kinase assays at 30 °C by adding [γ-32P]ATP and 2 μg of GST-IκBα (1-54)12.”
Muscles and their myokines (2011, background): “A number of studies both in vitro (Rotter et al., 2003; Lagathu et al., 2003; Senn et al., 2002; Senn et al., 2003) and in rodents in vivo (Klover et al., 2003; Klover et al., 2005; Kim et al., 2004) demonstrate that IL-6 is capable of inducing insulin resistance.”
Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics (2007, background): “IL-6 is well-documented to cause insulin-resistance in liver and fat [148, 149].”
IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. (2011, background): “As IL-6 induced insulin resistance in cell culture systems [64,65], it might play an important role in the development of diabetes in man.”
Senescence-messaging secretome: SMS-ing cellular stress (2009, background): “122 ), the latter inhibits phosphorylation of IRS1 in primary murine hepatocytes and hepatocellular carcinom”
The anti-inflammatory effect of exercise. (2005, background): “In vitro studies demonstrate that IL-6 can induce insulin resistance in isolated 3T3-L1 adipocytes (120) and in mice (61).”
Periodontitis and diabetes: a two-way relationship (2011, background): “TNF-α and IL-6 are the main inducers of acute-phase proteins, including CRP, and both have been shown to impair intracellular insulin signalling, potentially contributing to insulin resistance [44, 45].”