Activation of Peroxisome Proliferator–Activated Receptor-β/-δ (PPAR-β/-δ) Ameliorates Insulin Signaling and Reduces SOCS3 Levels by Inhibiting STAT3 in Interleukin-6–Stimulated Adipocytes
| Autor: | Walter Wahli, Liliane Michalik, Lucía Serrano-Marco, Xavier Palomer, Manuel Vázquez-Carrera, Ilhem El Kochairi, Ricardo Rodríguez-Calvo |
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| Rok vydání: | 2011 |
| Předmět: |
Male
STAT3 Transcription Factor medicine.medical_specialty Adipose Tissue White Endocrinology Diabetes and Metabolism Peroxisome proliferator-activated receptor Suppressor of Cytokine Signaling Proteins White adipose tissue Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation 3T3-L1 Cells Adipocyte Internal medicine Adipocytes Internal Medicine medicine Animals Insulin HSP90 Heat-Shock Proteins PPAR delta SOCS3 PPAR-beta 030304 developmental biology Mitogen-Activated Protein Kinase 1 chemistry.chemical_classification 0303 health sciences Mitogen-Activated Protein Kinase 3 biology Interleukin-6 digestive oral and skin physiology Adipocytes/drug effects Adipocytes/metabolism Adipose Tissue White/metabolism Glucose/metabolism HSP90 Heat-Shock Proteins/metabolism Insulin/physiology Interleukin-6/antagonists & inhibitors Interleukin-6/pharmacology Mitogen-Activated Protein Kinase 1/antagonists & inhibitors Mitogen-Activated Protein Kinase 3/antagonists & inhibitors PPAR delta/deficiency PPAR delta/metabolism PPAR-beta/metabolism Proto-Oncogene Proteins c-akt/metabolism Rats STAT3 Transcription Factor/antagonists & inhibitors Signal Transduction/drug effects Suppressor of Cytokine Signaling Proteins/metabolism Thiazoles/pharmacology Pharmacology and Therapeutics Thiazoles Insulin receptor Glucose Endocrinology chemistry 030220 oncology & carcinogenesis biology.protein Phosphorylation Peroxisome proliferator-activated receptor delta Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Diabetes r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname Diabetes, vol. 60, no. 7, pp. 1990-1999 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db10-0704 |
| Popis: | OBJECTIVE It has been suggested that interleukin (IL)-6 is one of the mediators linking obesity-derived chronic inflammation with insulin resistance through activation of STAT3, with subsequent upregulation of suppressor of cytokine signaling 3 (SOCS3). We evaluated whether peroxisome proliferator–activated receptor (PPAR)-β/-δ prevented activation of the IL-6-STAT3-SOCS3 pathway and insulin resistance in adipocytes. RESEARCH DESIGN AND METHODS Adipocytes and white adipose tissue from wild-type and PPAR-β/-δ-null mice were used to evaluate the effect of PPAR-β/-δ on the IL-6-STAT3-SOCS3 pathway. RESULTS First, we observed that the PPAR-β/-δ agonist GW501516 prevented both IL-6–dependent reduction in insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes. In addition, this drug treatment abolished IL-6–induced SOCS3 expression in differentiated 3T3-L1 adipocytes. This effect was associated with the capacity of the drug to prevent IL-6–induced STAT3 phosphorylation on Tyr705 and Ser727 residues in vitro and in vivo. Moreover, GW501516 prevented IL-6–dependent induction of extracellular signal–related kinase (ERK)1/2, a serine-threonine-protein kinase involved in serine STAT3 phosphorylation. Furthermore, in white adipose tissue from PPAR-β/-δ–null mice, STAT3 phosphorylation (Tyr705 and Ser727), STAT3 DNA-binding activity, and SOCS3 protein levels were higher than in wild-type mice. Several steps in STAT3 activation require its association with heat shock protein 90 (Hsp90), which was prevented by GW501516 as revealed in immunoprecipitation studies. Consistent with this finding, the STAT3-Hsp90 association was enhanced in white adipose tissue from PPAR-β/-δ–null mice compared with wild-type mice. CONCLUSIONS Collectively, our findings indicate that PPAR-β/-δ activation prevents IL-6–induced STAT3 activation by inhibiting ERK1/2 and preventing the STAT3-Hsp90 association, an effect that may contribute to the prevention of cytokine-induced insulin resistance in adipocytes. |
| Databáze: | OpenAIRE |
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