title: STAT6 promotes bi-directional modulation of PKM2 in liver and adipose inflammatory cells in rosiglitazone-treated mice.
abstract: STAT6 interacts with PPARγ to elicit macrophage polarization towards an anti-inflammatory, insulin-sensitizing phenotype. Mice deficient in STAT6 display liver lipid accumulation (hepatosteatosis). Rosiglitazone (RSG), a PPARγ agonist, ameliorates hepatosteatosis and enhances insulin sensitivity. To elucidate the role of STAT6 in PPARγ action on hepatosteatosis we compared liver proteomes of RSG-treated wild type and STAT6-deficient mice and we identified pyruvate kinase M2 (PKM2), a glycolysis and proliferation-regulating enzyme that displayed STAT6-dependent expression. RSG induced PKM2 within inflammatory cells in liver but suppressed its expression in adipose tissue. RSG diminished hepatosteatosis and oxidative stress, enhanced fat accumulation and improved insulin sensitivity in STAT6-deficient mice. Our data reveal a complex interaction between STAT6 and PPARγ in the regulation of liver and adipose tissue lipid depot distribution and design STAT6 as a novel link between inflammatory cell metabolism and adipocyte and hepatocyte function.
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, Geneva 4, Switzerland
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sajic
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hainard
authors.forename: Alexander
authors.initials: A
authors.lastname: Scherl
authors.forename: Annelise
authors.initials: A
authors.lastname: Wohlwend
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Sanchez
authors.forename: Ildiko
authors.initials: I
authors.lastname: Szanto
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020543:Proteome / Q000378:metabolism*; D000077154:Rosiglitazone; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D013963:Thyroid Hormones / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D020543:Proteome; D000077154:Rosiglitazone; D050800:STAT6 Transcription Factor; D045162:Thiazolidinediones; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C494100:Stat6 protein, mouse
references.citation: Oncol Rep. 2011 Jan;25(1):23-31
references.pmid: 21109953
references.citation: Annu Rev Physiol. 2010;72:219-46
references.pmid: 20148674
references.citation: Diabetes Obes Metab. 2003 Jul;5(4):234-43
references.pmid: 12795656
references.citation: Semin Cancer Biol. 2005 Aug;15(4):300-8
references.pmid: 15908230
references.citation: Mol Cell Proteomics. 2008 Jun;7(6):1174-85
references.pmid: 18344232
references.citation: Am J Respir Crit Care Med. 1999 Oct;160(4):1283-91
references.pmid: 10508820
references.citation: Immunol Res. 2011 May;50(1):87-96
references.pmid: 21442426
references.citation: F1000 Biol Rep. 2012;4:9
references.pmid: 22615715
references.citation: Histochem Cell Biol. 2009 Jun;131(6):713-26
references.pmid: 19255771
references.citation: J Clin Gastroenterol. 2002 May-Jun;34(5):582-4
references.pmid: 11960075
references.citation: J Mol Med (Berl). 1997 May;75(5):317-26
references.pmid: 9181473
references.citation: World J Gastroenterol. 2010 Oct 7;16(37):4652-60
references.pmid: 20872965
references.citation: Immunity. 1996 Mar;4(3):313-9
references.pmid: 8624821
references.citation: Cell Death Dis. 2012 Jan 12;3:e248
references.pmid: 22237205
references.citation: Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E287-91
references.pmid: 15637349
references.citation: Circ Res. 2010 May 28;106(10):1559-69
references.pmid: 20508200
references.citation: Diabetes. 2002 Mar;51(3):797-802
references.pmid: 11872682
references.citation: Physiol Rev. 2008 Jan;88(1):125-72
references.pmid: 18195085
references.citation: Basic Clin Pharmacol Toxicol. 2010 Aug;107(2):663-8
references.pmid: 20210788
references.citation: Immunity. 2010 Nov 24;33(5):699-712
references.pmid: 21093321
references.citation: Cardiovasc Diabetol. 2010 Oct 18;9:64
references.pmid: 20955583
references.citation: Nat Med. 2009 Aug;15(8):914-20
references.pmid: 19633658
references.citation: Proteomics. 2003 Aug;3(8):1500-20
references.pmid: 12923776
references.citation: PLoS One. 2009 Dec 24;4(12):e8196
references.pmid: 20041138
references.citation: Nat Commun. 2012 Feb 14;3:672
references.pmid: 22334075
references.citation: Diabetes. 1994 Nov;43(11):1271-8
references.pmid: 7926300
references.citation: Int J Biochem Cell Biol. 2011 Jul;43(7):969-80
references.pmid: 20156581
references.citation: N Engl J Med. 2004 Sep 9;351(11):1106-18
references.pmid: 15356308
references.citation: J Biol Chem. 2003 Sep 5;278(36):34268-76
references.pmid: 12805374
references.citation: Cell Metab. 2006 Jul;4(1):13-24
references.pmid: 16814729
references.citation: Hepatology. 2003 Oct;38(4):1008-17
references.pmid: 14512888
references.citation: J Proteome Res. 2009 Oct;8(10):4511-24
references.pmid: 19663508
references.citation: Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):619-26
references.pmid: 18838972
references.citation: J Clin Invest. 2003 Aug;112(4):608-18
references.pmid: 12925701
references.citation: J Clin Endocrinol Metab. 2004 Feb;89(2):463-78
references.pmid: 14764748
references.citation: J Neuroimmunol. 2011 Mar;232(1-2):26-34
references.pmid: 21051093
references.citation: Nat Rev Cancer. 2011 Feb;11(2):85-95
references.pmid: 21258394
references.citation: Am J Clin Pathol. 2007 Nov;128(5):837-47
references.pmid: 17951208
references.citation: Annu Rev Pathol. 2011;6:275-97
references.pmid: 21034223
references.citation: Int J Obes (Lond). 2012 Dec;36(12):1503-13
references.pmid: 22430302
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: ScientificWorldJournal. 2011;11:2509-29
references.pmid: 22235182
references.citation: J Clin Endocrinol Metab. 2007 Feb;92(2):386-95
references.pmid: 17148564
references.citation: Ernst Schering Found Symp Proc. 2007;(4):99-124
references.pmid: 18811055
references.citation: Nat Rev Immunol. 2002 Dec;2(12):933-44
references.pmid: 12461566
references.citation: Nature. 2007 Jun 28;447(7148):1116-20
references.pmid: 17515919
references.citation: Oncogene. 2006 Aug 7;25(34):4633-46
references.pmid: 16892078
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22617-22
references.pmid: 21149710
references.citation: Nature. 2008 Jul 24;454(7203):470-7
references.pmid: 18650918
references.citation: PLoS One. 2010 Feb 09;5(2):e9111
references.pmid: 20161756
references.citation: Diabetes. 2009 Nov;58(11):2574-82
references.pmid: 19690061
references.citation: Mol Cell Biochem. 2010 Nov;344(1-2):55-63
references.pmid: 20614231
references.citation: Anal Chem. 2003 Apr 15;75(8):1895-904
references.pmid: 12713048
references.citation: Obesity (Silver Spring). 2007 Nov;15(11):2653-63
references.pmid: 18070756
references.citation: Anal Chem. 2008 Apr 15;80(8):2921-31
references.pmid: 18312001
references.citation: Cytokine Growth Factor Rev. 2006 Jun;17(3):173-88
references.pmid: 16540365
references.citation: J Clin Endocrinol Metab. 2008 Jan;93(1):118-24
references.pmid: 17956948