Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.
Lucie OrliaguetT EjlalmaneshA HumbertR BallaireM DiedisheimJ B JullaD ChokrJ CuencoJ MichielettoJ CharbitDaniel LindénJ BoucherC PotierA HamimiSophie LemoineC BlugeonP LegoixS LameirasL G BaudrinSylvain BaulandeA SopraniF A CastelliFrançois FenailleJ P RivelineE DalmasJ RieussetJ F GautierNicolas VenteclefFawaz AlzaidPublished in: Nature communications (2022)
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.
Keyphrases
- dendritic cells
- transcription factor
- insulin resistance
- high fat diet induced
- adipose tissue
- oxidative stress
- metabolic syndrome
- weight loss
- type diabetes
- weight gain
- poor prognosis
- copy number
- immune response
- stem cells
- high fat diet
- skeletal muscle
- gene expression
- dna binding
- growth hormone
- genome wide
- binding protein
- dna damage
- small molecule
- body mass index
- peripheral blood
- amino acid
- human health
- heat shock
- blood brain barrier