title: Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet.
abstract: Low-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet(-/-) mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet(-/-) mice also lacking adaptive immunity (T-bet(-/-)xRag2(-/-)), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4(+) T cells to Rag2(-/-) mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance.
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London SE1 9RT, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Stolarczyk
authors.forename: Chi Teng
authors.initials: CT
authors.lastname: Vong
authors.forename: Esperanza
authors.initials: E
authors.lastname: Perucha
authors.forename: Ian
authors.initials: I
authors.lastname: Jackson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cawthorne
authors.forename: Edward T
authors.initials: ET
authors.lastname: Wargent
authors.forename: Nick
authors.initials: N
authors.lastname: Powell
authors.forename: James B
authors.initials: JB
authors.lastname: Canavan
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.forename: Jane K
authors.initials: JK
authors.lastname: Howard
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004734:Energy Metabolism; D007107:Immune System / Q000378:metabolism; D066298:In Vitro Techniques; D007333:Insulin Resistance; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
references.citation: Nat Med. 2011 May;17(5):610-7
references.pmid: 21499269
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1810-8
references.pmid: 17234956
references.citation: Cell Metab. 2008 May;7(5):410-20
references.pmid: 18460332
references.citation: J Allergy Clin Immunol. 2004 May;113(5):987-94
references.pmid: 15131585
references.citation: J Clin Invest. 2007 Jan;117(1):175-84
references.pmid: 17200717
references.citation: Mech Dev. 2002 Aug;116(1-2):157-60
references.pmid: 12128215
references.citation: Clin Exp Immunol. 2007 Apr;148(1):32-46
references.pmid: 17328715
references.citation: Nat Med. 2004 Jul;10(7):734-8
references.pmid: 15220914
references.citation: Cancer Cell. 2009 Sep 8;16(3):208-19
references.pmid: 19732721
references.citation: Am J Pathol. 2008 Jun;172(6):1500-8
references.pmid: 18467709
references.citation: J Exp Zool. 2002 Aug 15;294(2):112-21
references.pmid: 12210112
references.citation: FEBS Lett. 2005 Jul 4;579(17):3487-92
references.pmid: 15953605
references.citation: Arch Physiol Biochem. 2008 Jul;114(3):183-94
references.pmid: 18629684
references.citation: Lancet. 2008 Oct 11;372(9646):1281-3
references.pmid: 18929889
references.citation: Nat Med. 2009 Aug;15(8):930-9
references.pmid: 19633656
references.citation: Neural Syst Circuits. 2011 Feb 01;1(1):5
references.pmid: 22330144
references.citation: Circ Res. 2002 Aug 23;91(4):281-91
references.pmid: 12193460
references.citation: Biochem Biophys Res Commun. 2009 Jul 10;384(4):482-5
references.pmid: 19422792
references.citation: Cell. 2007 Oct 5;131(1):33-45
references.pmid: 17923086
references.citation: Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1304-10
references.pmid: 18420999
references.citation: Nat Med. 2009 Aug;15(8):914-20
references.pmid: 19633658
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17876-81
references.pmid: 19805038
references.citation: Blood. 2011 Apr 28;117(17):4511-8
references.pmid: 21389319
references.citation: Blood. 2008 Sep 1;112(5):1557-69
references.pmid: 18725574
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: J Physiol. 1949 Aug;109(1-2):1-9
references.pmid: 15394301
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7749-54
references.pmid: 12802010
references.citation: J Clin Invest. 2007 Sep;117(9):2621-37
references.pmid: 17717599
references.citation: Immunity. 2012 Oct 19;37(4):674-84
references.pmid: 23063332
references.citation: Nat Med. 2012 Mar 06;18(3):363-74
references.pmid: 22395709
references.citation: J Exp Med. 2004 Jul 5;200(1):79-87
references.pmid: 15238607
references.citation: Immunity. 2004 Apr;20(4):477-94
references.pmid: 15084276
references.citation: Nat Med. 2009 Aug;15(8):846-7
references.pmid: 19661987
references.citation: Diabetes. 2007 Sep;56(9):2242-50
references.pmid: 17473219
references.citation: Nat Med. 2009 Aug;15(8):921-9
references.pmid: 19633657
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15137-42
references.pmid: 11752460
references.citation: Blood. 2005 Nov 15;106(10):3432-9
references.pmid: 16014561
references.citation: Metabolism. 2012 Aug;61(8):1152-61
references.pmid: 22386937
references.citation: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):193-9
references.pmid: 19910631
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: Science. 2002 Jan 11;295(5553):338-42
references.pmid: 11786644
references.citation: Endocrinology. 2011 Oct;152(10):3690-9
references.pmid: 21791564
references.citation: J Immunol. 1996 Jan 1;156(1):5-7
references.pmid: 8598493
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Br J Nutr. 2013 May 28;109(10):1755-64
references.pmid: 23110765
references.citation: Nat Commun. 2012;3:1268
references.pmid: 23232398
references.citation: J Clin Invest. 1999 Oct;104(8):1051-9
references.pmid: 10525043
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: Circ Res. 2008 Aug 29;103(5):467-76
references.pmid: 18658050
references.citation: Nature. 1998 Aug 27;394(6696):897-901
references.pmid: 9732873