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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 the 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 membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-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 high-fat diet-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 the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Zhou H,Wang H,Yu M,Schugar RC,Qian W,Tang F,Liu W,Yang H,McDowell RE,Zhao J,Gao J,Dongre A,Carman JA,Yin M,Drazba JA,Dent R,Hine C,Chen YR,Smith JD,Fox PL,Brown JM,Li X

doi

10.1038/s41590-020-0750-1

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

1219-1231

issue

10

eissn

1529-2908

issn

1529-2916

pii

10.1038/s41590-020-0750-1

journal_volume

21

pub_type

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