title: Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice.
abstract: Leptin-deficient ob/ob mice are overweight, develop insulin resistance, and serve as a model for type 2 diabetes (T2D). Studies suggest that inflammatory pathways are linked to the development of insulin resistance and T2D both in animals and humans. We asked whether the induction of regulatory T cells (Tregs) could alleviate the pathological and metabolic abnormalities in ob/ob mice. We induced TGF-beta-dependent CD4(+) latency-associated peptide (LAP)-positive Tregs by oral administration of anti-CD3 antibody plus beta-glucosylceramide. We found a decrease in pancreatic islet cell hyperplasia, fat accumulation in the liver, and inflammation in adipose tissue, accompanied by lower blood glucose and liver enzymes. In addition, treated animals had decreased CD11b(+)F4/80(+) macrophages and TNF-alpha in adipose tissue. Adoptive transfer of orally induced CD4(+)LAP(+) Tregs ameliorated metabolic and cytokine abnormalities. Our results demonstrate the importance of inflammation in T2D and identify a unique immunological approach for treatment of T2D by the induction of Tregs.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
authors.forename: Ruth
authors.initials: R
authors.lastname: Maron
authors.forename: Ann-Marcia
authors.initials: AM
authors.lastname: Tukpah
authors.forename: Tatiani Uceli
authors.initials: TU
authors.lastname: Maioli
authors.forename: Gopal
authors.initials: G
authors.lastname: Murugaiyan
authors.forename: Kaiyong
authors.initials: K
authors.lastname: Yang
authors.forename: Henry Yim
authors.initials: HY
authors.lastname: Wu
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000273:Adipose Tissue / Q000276:immunology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology; D006965:Hyperplasia / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D055611:Natural Killer T-Cells / Q000276:immunology; D010179:Pancreas / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D001786:Blood Glucose; D002784:Cholesterol
references.citation: Trends Immunol. 2006 Jul;27(7):322-7
references.pmid: 16735139
references.citation: J Exp Med. 2007 Aug 6;204(8):1737-9
references.pmid: 17620364
references.citation: J Immunol. 2006 Nov 1;177(9):5997-6006
references.pmid: 17056524
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: Science. 1993 Jan 1;259(5091):87-91
references.pmid: 7678183
references.citation: Int Immunol. 2007 Aug;19(8):1021-9
references.pmid: 17698563
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: Nat Rev Immunol. 2007 Nov;7(11):875-88
references.pmid: 17948021
references.citation: Science. 1996 Nov 15;274(5290):1185-8
references.pmid: 8895466
references.citation: Nat Med. 2009 Aug;15(8):921-9
references.pmid: 19633657
references.citation: Annu Rev Med. 2006;57:381-402
references.pmid: 16409156
references.citation: Nat Rev Immunol. 2007 Aug;7(8):585-98
references.pmid: 17653126
references.citation: Nature. 2006 May 11;441(7090):235-8
references.pmid: 16648838
references.citation: Gut. 2007 Jan;56(1):82-9
references.pmid: 17172586
references.citation: J Biol Chem. 1993 Dec 15;268(35):26055-8
references.pmid: 8253716
references.citation: Nat Med. 2009 Aug;15(8):930-9
references.pmid: 19633656
references.citation: Lupus. 2009 Jun;18(7):586-96
references.pmid: 19433458
references.citation: J Immunol. 2006 Sep 1;177(5):2899-907
references.pmid: 16920925
references.citation: Annu Rev Immunol. 2007;25:297-336
references.pmid: 17150027
references.citation: Immunology. 2006 May;118(1):101-11
references.pmid: 16630027
references.citation: Nat Med. 2009 Aug;15(8):914-20
references.pmid: 19633658
references.citation: Inflamm Bowel Dis. 2003 Mar;9(2):75-86
references.pmid: 12769441
references.citation: Curr Opin Gastroenterol. 2006 Jul;22(4):354-60
references.pmid: 16760749
references.citation: Nat Med. 2006 Jun;12(6):627-35
references.pmid: 16715091
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Nov;289(5):G917-25
references.pmid: 15976388
references.citation: Diabetes. 2007 Aug;56(8):2103-9
references.pmid: 17456848
references.citation: Curr Top Microbiol Immunol. 2007;312:101-36
references.pmid: 17089795
references.citation: Cytokine Growth Factor Rev. 1999 Jun;10(2):99-117
references.pmid: 10743502
references.citation: Int Rev Immunol. 2005 May-Aug;24(3-4):247-67
references.pmid: 16036377
references.citation: J Clin Invest. 2003 Dec;112(12):1785-8
references.pmid: 14679172
references.citation: Immunol Rev. 2005 Aug;206:232-59
references.pmid: 16048553
references.citation: Immunol Rev. 2006 Aug;212:203-16
references.pmid: 16903916
references.citation: Mini Rev Med Chem. 2006 Nov;6(11):1249-53
references.pmid: 17100636
references.citation: J Exp Med. 1996 Aug 1;184(2):387-96
references.pmid: 8760792
references.citation: Science. 1995 Jul 28;269(5223):540-3
references.pmid: 7624776
references.citation: J Clin Invest. 2005 May;115(5):1111-9
references.pmid: 15864338
references.citation: Nat Immunol. 2007 Dec;8(12):1380-9
references.pmid: 17994022
references.citation: J Clin Invest. 2002 May;109(10):1321-6
references.pmid: 12021247
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13998-4003
references.pmid: 19666548
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: J Pharmacol Exp Ther. 2006 Oct;319(1):105-10
references.pmid: 16815870
references.citation: J Immunol. 2003 Mar 1;170(5):2516-22
references.pmid: 12594277
references.citation: J Immunol. 2010 May 1;184(9):4620-4
references.pmid: 20368276
references.citation: J Immunol. 2008 Nov 1;181(9):6038-50
references.pmid: 18941193