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Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity

Nature Medicine volume 21, pages 610–618 (2015)Cite this article

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Abstract

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.

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Figure 1: Irf5 is specifically induced in visceral adipose tissue macrophages during obesity.
Figure 2: Irf5 deficiency promotes intra-abdominal adipose tissue remodeling and type 2 immune responses while enhancing inguinal adiposity.
Figure 3: Myeloid cell–specific Irf5 deletion promotes subcutaneous adiposity and intra-abdominal adipose tissue remodeling.
Figure 4: Irf5 depletion preserves glucose homeostasis in obesity.
Figure 5: IRF5 expression in macrophages is associated with adipose tissue collagen deposition in human obesity.
Figure 6: IRF5 controls transcription of the TGFB1 gene in human adipose-tissue macrophages.

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Acknowledgements

We are grateful to C. Enond and H. Foher-Ting. We thank Assistance Publique des Hôpitaux de Paris, Programs of Clinical Investigation (Contrat de Recherche Clinique Fibrota AOO759-32 PI to J.A.-W. and Programme Hospitalier de Recherche Clinique 0702 PI to K.C.), the French National Agency of Research (CONRAD to N. Venteclef, ADIPOFIB to K.C. and OBELIP to D.L.), a fellowship from Region Ile de France (to F.A., N. Venteclef and K.C.), Midi-Pyrénées (to D.L.), and the French Foundation for Medical Research (Equipe FRM DEQ20140329504 to F.F. and N. Venteclef and Equipe FRM DEQ20120323701 to K.C.). This work has benefited from a French Government grant managed by the National Agency for Research ('Investments for the Future' program, reference no. ANR-10-IAHU (to K.C. and F.F.) and from the Kennedy Institute Trustees' Research Fund (to K.B., H.L.E. and I.A.U.). Metabolic analyses in vivo were performed on the Functional & Physiological Exploration Platform (FPE) technical platform, unit 'Biologie Fonctionnelle et Adaptative,' (Univ. Paris Diderot, Sorbonne Paris Cité, Paris, France), and on the ICAN PRECLINIC platform (Institute of Cardiometabolism and Nutrition, Pitie-Salpêtrière Hospital, Paris, France). D.L. is a member of Institut Universitaire de France. A. Toubal is a recipient of a doctoral fellowship from the Ministère de la Recherche et de l'Enseignement Supérieur.

Author information

Author notes

  1. Elise Dalmas, Amine Toubal and Fawaz Alzaid: These authors contributed equally to this work.

Authors and Affiliations

  1. Sorbonne Universités, Université Pierre et Marie-Curie; INSERM UMR_S 1166-ICAN, Nutriomics,

    Elise Dalmas, Amine Toubal, Maria Pini, Patricia Ancel, Yin Ling, Omran Allatif, Sébastien André, Christine Poitou, Judith Aron-Wisnewsky & Karine Clément

  2. INSERM UMR_S 1166-ICAN, Nutriomics, Paris, France

    Elise Dalmas, Amine Toubal, Maria Pini, Patricia Ancel, Yin Ling, Omran Allatif, Sébastien André, Christine Poitou, Judith Aron-Wisnewsky & Karine Clément

  3. Institute of Cardiometabolism and Nutrition, Paris, France

    Elise Dalmas, Amine Toubal, Fawaz Alzaid, Kristell Lebozec, Maria Pini, Isabelle Hainault, Patricia Ancel, Amélie Lacombe, Yin Ling, Omran Allatif, Sébastien André, Christine Poitou, Fabienne Foufelle, Judith Aron-Wisnewsky, Karine Clément & Nicolas Venteclef

  4. Sorbonne Universités, Université Pierre et Marie-Curie, INSERM, UMR_S 1138 Cordeliers Research Center, Paris, France

    Amine Toubal, Fawaz Alzaid, Kristell Lebozec, Isabelle Hainault, Fabienne Foufelle & Nicolas Venteclef

  5. Kennedy Institute Trust of Rheumatology, University of Oxford, Oxford, UK

    Katrina Blazek, Hayley L Eames & Irina A Udalova

  6. INSERM, University of Toulouse, Paul Sabatier University, UMR 1048, Toulouse, France

    Emilie Montastier

  7. Department of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France

    Emilie Montastier & Nathalie Viguerie

  8. Department of Nutrition, Toulouse University Hospitals, Toulouse, France

    Emilie Montastier & Nathalie Viguerie

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

    Raphaël G P Denis, Céline Cruciani-Guglielmacci & Serge Luquet

  10. Heart and Metabolism Division, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

    Christine Poitou, Judith Aron-Wisnewsky, Dominique Langin & Karine Clément

  11. Department of Sports Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

    Vladimir Stich & Dominique Langin

  12. Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

    Vladimir Stich

  13. Visceral Surgery Division, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

    Alexandra Torcivia

Authors
  1. Elise Dalmas
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  2. Amine Toubal
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Contributions

E.D., I.A.U. and N. Venteclef conceived the study and wrote the manuscript. E.D. performed part of the in vivo studies (human and mouse) and analyzed data. A. Toubal and F.A. performed the in vivo studies and data analyses, and assisted in the preparation of the manuscript. K.B., H.L.E., M.P., I.H., Y.L. and P.A. assisted with the mouse studies. S.A. and K.L. assisted with flow cytometry analyses. A.L., R.G.P.D. and C.C.-G. performed the metabolic analyses in vivo. E.M., N. Viguerie, C.P., V.S., A. Torcivia, J.A.-W., D.L. and K.C. contributed to the human data collection, data analyses and interpretation. O.A. and K.C. performed statistical analyses in population 1. F.F., S.L., J.A.-W., D.L. and K.C. interpreted and assisted in the writing of the manuscript. I.A.U. and N. Venteclef designed, analyzed and interpreted the studies.

Corresponding authors

Correspondence to Irina A Udalova or Nicolas Venteclef.

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Dalmas, E., Toubal, A., Alzaid, F. et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med 21, 610–618 (2015). https://doi.org/10.1038/nm.3829

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