Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2022

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

J. Michieletto
  • Function : Author
J. Charbit
  • Function : Author
D. Lindén
J. Boucher
  • Function : Author
S. Lemoine
C. Blugeon
P. Legoix
  • Function : Author
S. Lameiras
  • Function : Author
L. Baudrin
  • Function : Author
S. Baulande
F. Castelli
  • Function : Author
J. Rieusset
  • Function : Author

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.
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hal-03770463 , version 1 (06-09-2023)

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L. Orliaguet, T. Ejlalmanesh, A. Humbert, R. Ballaire, M. Diedisheim, et al.. Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling. Nature Communications, 2022, 13 (1), pp.5089. ⟨10.1038/s41467-022-32813-z⟩. ⟨hal-03770463⟩
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