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

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.

The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infection

“…A recent study by Orliaguet et al . has shown that IRF-5 regulates the mitochondrial architecture remodelling by transcriptionally repressing a key mitochondrial component for oxidative respiration, namely GHITM (55). This work was done in macrophages and in the context of a high-fat diet.…”

“…The second study by Orliaguet et al demonstrates that IRF-5-deficient macrophages have a highly oxidative nature in the context of a short-term high fat diet. This was caused by transcriptional de-repression of the mitochondrial matrix component Ghitm , which is a direct target of IRF-5 (55). GHITM is an inner membrane protein that maintains mitochondrial architecture for efficient oxidative phosphorylation (61) and de-repression of Ghitm in Irf5 -/- macrophages results in an increased oxygen consumption rate (55).…”

“…This was caused by transcriptional de-repression of the mitochondrial matrix component Ghitm , which is a direct target of IRF-5 (55). GHITM is an inner membrane protein that maintains mitochondrial architecture for efficient oxidative phosphorylation (61) and de-repression of Ghitm in Irf5 -/- macrophages results in an increased oxygen consumption rate (55). In our model, IRF-5-deficient p14 CD8 T cell do not display a higher oxygen consumption rate upon in vitro stimulation with the gp33 peptide.…”

Unraveling Verapamil’s Multidimensional Role in Diabetes Therapy: From β-Cell Regeneration to Cholecystokinin Induction in Zebrafish and MIN6 Cell-Line Models

“…At the end point of each condition, an OCR assay was performed using compounds in assay media (supplemented with 5.6 mM glucose) at the following concentrations: Oligomycin (1 µM), FCCP (2 µM), and Rot/AA (0.5 µM) (Cat# 103015-100; Agilent Technologies Seahorse XF Cell Mito Stress Test Kit, Santa Clara, CA, USA). The levels of basal and maximal respirations were calculated, and OCR was normalized to the extracted total protein as an indirect estimation of the number of cells [ 30 ].…”

Unraveling Verapamil's Multidimensional Role in Diabetes Therapy: From β-Cell Regeneration to Cholecystokinin Induction

“…At the end point of each condition, an OCR assay was performed using compounds in assay media (supplemented with 5.6 mM glucose) at the following concentrations: Oligomycin (1 μM), FCCP (2 μM), and Rot/AA (0.5 μM) (Cat# 103015-100; Agilent Technologies Seahorse XF Cell Mito Stress Test Kit, Santa Clara, CA, USA). The levels of basal and maximal respirations were calculated, and OCR was normalized by the number of cells [30].…”