Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Year: 2022
Type: article
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.
Source: Nature Communications
Authors: 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, F. Alzaid
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Cité, Sorbonne Université, Institut Necker Enfants Malades, Centre de Recherche des Cordeliers, Lyon 1 Université, Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Hôpital Lariboisière, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, CEA Paris-Saclay, MetaboHUB, Médicaments et Technologies pour la Santé, Hôpital Avicenne, AstraZeneca (Sweden), Université Paris Sciences et Lettres, École Normale Supérieure - PSL, Institut de Biologie de l'École Normale Supérieure, Institut Curie, Générale de Santé, Dasman Diabetes Institute
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: G1554707310, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique, G2579310621, Mitochondrial bioenergetics of metabolic inflammation: Derepressing mitochondrial respiration as a novel therapeutic approach in type-2 diabetes, G4072984709, G449165211, INSTITUTE OF INFLAMMATORY DISEASES, G6062526893, Targeting PUFA metabolism in MAcrophages In cardiovascular diseases, G705061367, G7240651115, G786270660, G7999552054, G8510727784, Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation
OpenAlex ID: W4293661003