Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling

L. Orliaguet, T. Ejlalmanesh, A. Humbert, R. Ballaire, M. Diedisheim, J. B. Julla, D. Chokr, J. Cuenco, J. Michieletto, J. Charbit, D. Lindén, J. Boucher, C. Potier, A. Hamimi, S. Lemoine, C. Blugeon, P. Legoix, S. Lameiras, L. G. Baudrin, S. Baulande, A. Soprani, F. A. Castelli, F. Fenaille, J. P. Riveline, E. Dalmas, J. Rieusset, J. F. Gautier, N. Venteclef () and F. Alzaid ()
Additional contact information
L. Orliaguet: Université Paris Cité, Institut Necker Enfants Malades
T. Ejlalmanesh: Université Paris Cité, Institut Necker Enfants Malades
A. Humbert: Lyon 1 University
R. Ballaire: Université Paris Cité, Institut Necker Enfants Malades
M. Diedisheim: Université Paris Cité, Institut Necker Enfants Malades
J. B. Julla: Université Paris Cité, Institut Necker Enfants Malades
D. Chokr: Université Paris Cité, Institut Necker Enfants Malades
J. Cuenco: Université Paris Cité, Institut Necker Enfants Malades
J. Michieletto: Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB
J. Charbit: Service d’endocrinologie, diabétologie, maladies métaboliques, Hôpital Avicenne
D. Lindén: BioPharmaceuticals R&D, AstraZeneca
J. Boucher: BioPharmaceuticals R&D, AstraZeneca
C. Potier: Université Paris Cité, Institut Necker Enfants Malades
A. Hamimi: Université Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, IMMEDIAB Laboratory
S. Lemoine: INSERM, Université PSL
C. Blugeon: INSERM, Université PSL
P. Legoix: PSL University
S. Lameiras: PSL University
L. G. Baudrin: PSL University
S. Baulande: PSL University
A. Soprani: Université Paris Cité, Institut Necker Enfants Malades
F. A. Castelli: Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB
F. Fenaille: Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB
J. P. Riveline: Université Paris Cité, Institut Necker Enfants Malades
E. Dalmas: Université Paris Cité, Institut Necker Enfants Malades
J. Rieusset: Lyon 1 University
J. F. Gautier: Université Paris Cité, Institut Necker Enfants Malades
N. Venteclef: Université Paris Cité, Institut Necker Enfants Malades
F. Alzaid: Université Paris Cité, Institut Necker Enfants Malades

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.

Date: 2022
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DOI: 10.1038/s41467-022-32813-z

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