Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity.
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.
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Elise
E
Dalmas
1] 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.
Amine
A
Toubal
1] Institute of Cardiometabolism and Nutrition, Paris, France. [2] Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France.
Fawaz
F
Alzaid
Kennedy Institute Trust of Rheumatology, University of Oxford, Oxford, UK.
Katrina
K
Blazek
Kennedy Institute Trust of Rheumatology, University of Oxford, Oxford, UK.
Hayley L
HL
Eames
1] Institute of Cardiometabolism and Nutrition, Paris, France. [2] Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France.
Kristell
K
Lebozec
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Maria
M
Pini
1] Institute of Cardiometabolism and Nutrition, Paris, France. [2] Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France.
Isabelle
I
Hainault
1] 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.
Emilie
E
Montastier
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
Raphaël G P
RG
Denis
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Patricia
P
Ancel
Institute of Cardiometabolism and Nutrition, Paris, France.
Amélie
A
Lacombe
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Yin
Y
Ling
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Omran
O
Allatif
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
Céline
C
Cruciani-Guglielmacci
1] Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France. [2] Institute of Cardiometabolism and Nutrition, Paris, France.
Sébastien
S
André
1] Department of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France. [2] Department of Nutrition, Toulouse University Hospitals, Toulouse, France.
Nathalie
N
Viguerie
1] 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.
Christine
C
Poitou
1] Department of Sports Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. [2] Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Vladimir
V
Stich
Visceral Surgery Division, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Alexandra
A
Torcivia
1] Institute of Cardiometabolism and Nutrition, Paris, France. [2] Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France.
Fabienne
F
Foufelle
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
Serge
S
Luquet
1] 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.
Judith
J
Aron-Wisnewsky
1] Heart and Metabolism Division, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. [2] Department of Sports Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Dominique
D
Langin
1] 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.
Karine
K
Clément
Kennedy Institute Trust of Rheumatology, University of Oxford, Oxford, UK.
Irina A
0000000267162528
IA
Udalova
1] Institute of Cardiometabolism and Nutrition, Paris, France. [2] Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France.
Nicolas
N
Venteclef
D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008264:Macrophages; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1