Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor β1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.

] Department of Clinical Biochemistry Toulouse University Hospitals Toulouse France [2] Department of Nutrition Toulouse University Hospitals Toulouse France

] Department of Sports Medicine 3rd Faculty of Medicine Charles University Prague Prague Czech Republic [2] Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine Charles University Prague Prague Czech Republic

] Heart and Metabolism Division Pitié Salpêtrière Hospital Assistance Publique Hôpitaux de Paris Paris France [2] Department of Sports Medicine 3rd Faculty of Medicine Charles University Prague Prague Czech Republic

] INSERM University of Toulouse Paul Sabatier University UMR 1048 Toulouse France [2] Department of Clinical Biochemistry Toulouse University Hospitals Toulouse France [3] Department of Nutrition Toulouse University Hospitals Toulouse France

] Institute of Cardiometabolism and Nutrition Paris France [2] Sorbonne Universités Université Pierre et Marie Curie INSERM UMR_S 1138 Cordeliers Research Center Paris France

] Sorbonne Universités Université Pierre et Marie Curie; INSERM UMR_S 1166 ICAN Nutriomics Paris France [2] Institute of Cardiometabolism and Nutrition Paris France

] Sorbonne Universités Université Pierre et Marie Curie; INSERM UMR_S 1166 ICAN Nutriomics Paris France [2] Institute of Cardiometabolism and Nutrition Paris France [3] Heart and Metabolism Division Pitié Salpêtrière Hospital Assistance Publique Hôpitaux de Paris Paris France

] Sorbonne Universités Université Pierre et Marie Curie; INSERM UMR_S 1166 ICAN Nutriomics Paris France [2] Institute of Cardiometabolism and Nutrition Paris France [3] Sorbonne Universités Université Pierre et Marie Curie INSERM UMR_S 1138 Cordeliers Research Center Paris France

Institute of Cardiometabolism and Nutrition Paris France

Kennedy Institute Trust of Rheumatology University of Oxford Oxford UK

Université Paris Diderot Sorbonne Paris Cité Unité de Biologie Fonctionnelle et Adaptative CNRS UMR 8251 Paris France

Visceral Surgery Division Pitié Salpêtrière Hospital Assistance Publique Hôpitaux de Paris Paris France

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Int J Obes Relat Metab Disord. 1994 Aug;18(8):532-6 PubMed

Nat Med. 2007 Nov;13(11):1324-32 PubMed

Nat Genet. 2006 May;38(5):550-5 PubMed

Neurosci Biobehav Rev. 1994 Fall;18(3):435-47 PubMed

Cell Metab. 2014 Jul 1;20(1):103-18 PubMed

Diabetes. 2010 Jan;59(1):105-9 PubMed

Nat Immunol. 2011 Mar;12(3):231-8 PubMed

J Clin Invest. 2011 Jul;121(7):2736-49 PubMed

Proc Natl Acad Sci U S A. 1985 Dec;82(24):8530-4 PubMed

Nature. 2005 Mar 10;434(7030):243-9 PubMed

Int J Obes (Lond). 2006 Sep;30(9):1322-31 PubMed

Diabetes. 2011 Mar;60(3):797-809 PubMed

Gastroenterology. 2013 Aug;145(2):366-74.e1-3 PubMed

Cell Rep. 2014 May 22;7(4):1116-29 PubMed

Cell. 2006 May 5;125(3):577-91 PubMed

PLoS One. 2011 Apr 12;6(4):e18284 PubMed

Cell Metab. 2013 Dec 3;18(6):816-30 PubMed

Endocrinology. 2014 Sep;155(9):3409-20 PubMed

PLoS Pathog. 2013 Jan;9(1):e1003118 PubMed

Am J Physiol Endocrinol Metab. 2010 Sep;299(3):E506-15 PubMed

Science. 2013 Jan 11;339(6116):172-7 PubMed

J Clin Endocrinol Metab. 2011 Dec;96(12):E1990-8 PubMed

J Clin Endocrinol Metab. 2011 Jan;96(1):E73-82 PubMed

Nutrition. 1990 May-Jun;6(3):213-21 PubMed

J Clin Invest. 1995 Jul;96(1):88-98 PubMed

Diabetologia. 2010 Dec;53(12):2496-503 PubMed

Circulation. 2008 Feb 12;117(6):806-15 PubMed

Diabetes. 2014 Jun;63(6):1966-77 PubMed

Diabetes. 2010 Nov;59(11):2817-25 PubMed

Semin Liver Dis. 2010 Aug;30(3):245-57 PubMed

J Hepatol. 2012 May;56(5):1152-8 PubMed

J Clin Invest. 2007 Sep;117(9):2621-37 PubMed

EMBO J. 2012 Nov 14;31(22):4276-88 PubMed

Diabetes Care. 2013 Feb;36(2):289-93 PubMed

Science. 2011 Apr 8;332(6026):243-7 PubMed

Diabetes. 2012 Sep;61(9):2238-47 PubMed

Genome Biol. 2008 Jan 21;9(1):R14 PubMed

Diabetologia. 1998 Jul;41(7):821-8 PubMed

Bioinformatics. 2008 Nov 15;24(22):2636-8 PubMed

Mol Cell Biol. 2009 Mar;29(6):1575-91 PubMed

Diabetes. 2008 Jul;57(7):1790-9 PubMed

Cell Metab. 2013 Oct 1;18(4):470-7 PubMed

J Clin Invest. 2009 May;119(5):1201-15 PubMed

Nature. 2007 Jun 28;447(7148):1116-20 PubMed

Endocrinology. 2013 Mar;154(3):1069-79 PubMed

Nat Rev Immunol. 2011 Oct 25;11(11):750-61 PubMed

Diabetologia. 2011 Apr;54(4):876-87 PubMed

Mol Cell Biol. 2009 Aug;29(16):4467-83 PubMed

Cell Immunol. 2000 Aug 25;204(1):19-28 PubMed

J Clin Invest. 2013 Jan;123(1):362-79 PubMed

Mol Endocrinol. 2009 Jan;23(1):11-24 PubMed

Physiol Rev. 2013 Jan;93(1):359-404 PubMed

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