IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes.

Abstract

Chronic inflammation is a common feature of obesity with elevated cytokines such as Interleukin-1 (IL-1) in circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2-Myddosome to mitochondria outer membrane via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membrane to suppress oxidative phosphorylation and fatty acid oxidation, thereby, attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high fat diet (HFD)-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced HFD-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.