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.

脂肪组织巨噬细胞 (ATM) 适应其能量微环境的变化。热量过剩，从短暂性肥胖到饮食引起的肥胖，可能导致 ATM 从高度氧化和保护性转变为高度炎症性和代谢有害。在这里，我们证明干扰素调节因子 5 (IRF5) 是响应热量过剩的巨噬细胞氧化能力的关键调节因子。来自Irf5基因缺陷小鼠的 ATM的特点是氧化呼吸和线粒体膜电位增加。IRF5 活性的瞬时抑制导致与基因组缺失相似的呼吸表型，并且可通过 IRF5 表达的重建而逆转。我们发现Irf5的高度氧化性- 巨噬细胞缺陷是由于线粒体基质成分生长激素诱导跨膜蛋白 (GHITM) 基因的转录去抑制所致。Irf5缺乏相关的高耗氧量可以通过实验抑制Ghitm表达来缓解。来自肥胖或 2 型糖尿病患者的 ATM 和单核细胞保留了Irf5和Ghitm之间的相互调节关系。因此，我们的研究提供了关于炎症转录因子 IRF5 如何通过调节巨噬细胞中的线粒体结构来控制对饮食诱导的肥胖的生理适应的机制的见解。