Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes

• Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.

Nyckelord

3T3-L1 Cells

Adipocytes/*metabolism/pathology

Animals

Anti-Inflammatory Agents

Non-Steroidal/pharmacology

Inflammation Mediators/*physiology

Insulin/*physiology

Interleukin-6/*antagonists & inhibitors/physiology

Intracellular Fluid/metabolism

Mice

Phosphorylation

STAT3 Transcription Factor/metabolism

Signal Transduction/*physiology

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