title: 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.
abstract: 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.
  
  
  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 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.
authors: Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, University of Barcelona, Institut de Biomedicina de la UB (IBUB), Barcelona, Spain.
authors: Lucía
authors: L
authors: Serrano-Marco
authors: Ricardo
authors: R
authors: Rodríguez-Calvo
authors: Ilhem
authors: I
authors: El Kochairi
authors: Xavier
authors: X
authors: Palomer
authors: Liliane
authors: L
authors: Michalik
authors: Walter
authors: W
authors: Wahli
authors: Manuel
authors: M
authors: Vázquez-Carrera
references: Cell. 1995 Jul 28;82(2):241-50
references: 7543024
references: Nature. 2005 Sep 29;437(7059):759-63
references: 16127449
references: Stem Cells. 2001;19(5):378-87
references: 11553846
references: Diabetes. 2007 Mar;56(3):795-803
references: 17327450
references: Nature. 1997 Jun 26;387(6636):917-21
references: 9202125
references: Diabetes. 2008 Aug;57(8):2149-57
references: 18443198
references: Am J Physiol Endocrinol Metab. 2001 May;280(5):E745-51
references: 11287357
references: Biotechniques. 1999 Jan;26(1):112-22, 124-5
references: 9894600
references: J Clin Endocrinol Metab. 2002 May;87(5):2084-9
references: 11994345
references: Biochem J. 2003 Aug 15;374(Pt 1):1-20
references: 12773095
references: J Dermatol Sci. 2009 Nov;56(2):121-7
references: 19734018
references: Endocrinology. 2007 Jun;148(6):2994-3003
references: 17379643
references: Nature. 2006 Dec 14;444(7121):860-7
references: 17167474
references: Diabetes. 2006 Mar;55(3):699-707
references: 16505233
references: Cell. 1999 Apr 16;97(2):161-3
references: 10219237
references: Endocrinology. 2005 Jul;146(7):3087-95
references: 15802498
references: Oncogene. 2000 May 15;19(21):2628-37
references: 10851062
references: J Biol Chem. 2001 Jul 13;276(28):25889-93
references: 11342531
references: Endocrinology. 2005 Aug;146(8):3417-27
references: 15845623
references: J Biol Chem. 2000 May 26;275(21):15985-91
references: 10821852
references: Science. 1995 Mar 31;267(5206):1990-4
references: 7701321
references: J Biol Chem. 2002 Nov 22;277(47):45662-9
references: 12235142
references: J Lipid Res. 2004 Jan;45(1):113-23
references: 14563825
references: J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):99-105
references: 15860251
references: J Biol Chem. 2008 Jan 11;283(2):708-15
references: 17993646
references: Ann N Y Acad Sci. 1990;594:214-21
references: 2198839
references: Nat Rev Immunol. 2002 Oct;2(10):748-59
references: 12360213
references: J Biol Chem. 2001 Dec 21;276(51):47944-9
references: 11604392
references: Biochem Biophys Res Commun. 2003 Jan 24;300(4):847-52
references: 12559950
references: Science. 1993 Jan 1;259(5091):87-91
references: 7678183
references: J Exp Med. 2001 Jan 15;193(2):263-9
references: 11208867
references: Biochem Biophys Res Commun. 2003 Nov 14;311(2):372-9
references: 14592424
references: Horm Metab Res. 2008 Jan;40(1):8-12
references: 18085494
references: Science. 2003 Oct 17;302(5644):453-7
references: 12970571
references: Mol Cell Biol. 1997 Nov;17(11):6508-16
references: 9343414
references: J Biol Chem. 2002 Nov 1;277(44):42394-8
references: 12228220
references: Rev Physiol Biochem Pharmacol. 2003;149:1-38
references: 12687404
references: Trends Genet. 2004 Jan;20(1):23-32
references: 14698616
references: J Clin Endocrinol Metab. 2001 Mar;86(3):1154-9
references: 11238501
references: J Biol Chem. 2006 Oct 20;281(42):31369-79
references: 16926159
references: J Biol Chem. 2004 Aug 13;279(33):34733-40
references: 15181014
references: Oncogene. 2000 May 15;19(21):2468-73
references: 10851045
references: Diabetes. 2006 Oct;55(10):2779-87
references: 17003343
references: J Biol Chem. 2003 Feb 14;278(7):4467-73
references: 12482853
references: J Clin Endocrinol Metab. 2001 May;86(5):2281-8
references: 11344240
references: J Clin Invest. 2006 Mar;116(3):590-7
references: 16511591
references: Obes Res. 2001 Jul;9(7):414-7
references: 11445664
references: Mol Cell Biol. 2006 Apr;26(8):3266-81
references: 16581799
references: Eur J Clin Invest. 2007 May;37(5):425-33
references: 17461989
references: JAMA. 2001 Jul 18;286(3):327-34
references: 11466099
references: Pharmacol Rev. 2006 Dec;58(4):726-41
references: 17132851
references: Immunity. 2004 Feb;20(2):205-18
references: 14975242
references: Nature. 1996 Nov 7;384(6604):39-43
references: 8900274