The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells

• Published in: Diabetologia 2012-03, Vol.55 (3), p.743-751
• Main Authors: Serrano-Marco, L., Barroso, E., El Kochairi, I., Palomer, X., Michalik, L., Wahli, W., Vázquez-Carrera, M.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation - drug effects; Hep G2 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Human Physiology; Humans; Insulin Resistance; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Knockout; Phosphorylation - drug effects; PPAR delta - agonists; PPAR delta - genetics; PPAR delta - metabolism; PPAR-beta - agonists; PPAR-beta - genetics; PPAR-beta - metabolism; Protein Processing, Post-Translational - drug effects; Protein Transport - drug effects; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Thiazoles - pharmacology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2401-4

Aim/hypothesis IL-6 induces insulin resistance by activating signal transducer and activator of transcription 3 (STAT3) and upregulating the transcription of its target gene SOCS3 . Here we examined whether the peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW501516 prevented activation of the IL-6–STAT3–suppressor of cytokine signalling 3 (SOCS3) pathway and insulin resistance in human hepatic HepG2 cells. Methods Studies were conducted with human HepG2 cells and livers from mice null for Pparβ/δ (also known as Ppard ) and wild-type mice. Results GW501516 prevented IL-6-dependent reduction in insulin-stimulated v-akt murine thymoma viral oncogene homologue 1 (AKT) phosphorylation and in IRS-1 and IRS-2 protein levels. In addition, treatment with this drug abolished IL-6-induced STAT3 phosphorylation of Tyr 705 and Ser 727 and prevented the increase in SOCS3 caused by this cytokine. Moreover, GW501516 prevented IL-6-dependent induction of extracellular-related kinase 1/2 (ERK1/2), a serine–threonine protein kinase involved in serine STAT3 phosphorylation; the livers of Pparβ/δ- null mice showed increased Tyr 705 - and Ser 727 -STAT3 as well as phospho-ERK1/2 levels. Furthermore, drug treatment prevented the IL-6-dependent reduction in phosphorylated AMP-activated protein kinase (AMPK), a kinase reported to inhibit STAT3 phosphorylation on Tyr 705 . In agreement with the recovery in phospho-AMPK levels observed following GW501516 treatment, this drug increased the AMP/ATP ratio and decreased the ATP/ADP ratio. Conclusions/interpretation Overall, our findings show that the PPARβ/δ activator GW501516 prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 phosphorylation and preventing the reduction in phospho-AMPK levels. These effects of GW501516 may contribute to the prevention of cytokine-induced insulin resistance in hepatic cells.