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.

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_3E0DBA597899
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
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.
Périodique
Diabetes
Auteur(s)
Serrano-Marco L., Rodríguez-Calvo R., El Kochairi I., Palomer X., Michalik L., Wahli W., Vázquez-Carrera M.
ISSN
1939-327X (Electronic)
ISSN-L
0012-1797
Statut éditorial
Publié
Date de publication
2011
Volume
60
Numéro
7
Pages
1990-1999
Langue
anglais
Résumé
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 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 Tyr(705) and Ser(727) 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 (Tyr(705) and Ser(727)), 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.
Mots-clé
3T3-L1 Cells, Adipocytes/drug effects, Adipocytes/metabolism, Adipose Tissue, White/metabolism, Animals, Glucose/metabolism, HSP90 Heat-Shock Proteins/metabolism, Insulin/physiology, Interleukin-6/antagonists & inhibitors, Interleukin-6/pharmacology, Male, Mice, 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
Pubmed
Web of science
Open Access
Oui
Création de la notice
06/06/2011 8:26
Dernière modification de la notice
20/08/2019 14:34
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