DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway

Juli Bai, Christopher Cervantes, Juan Liu, Sijia He, Haiyan Zhou, Bilin Zhang, Huan Cai, Dongqing Yin, Derong Hu, Zhi Li, Hongzhi Chen, Xiaoli Gao, Fang Wang, Jason C. O’Connor, Yong Xu, Meilian Liu, Lily Q. Dong, Feng Liu

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.

Original languageEnglish (US)
Pages (from-to)12196-12201
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number46
DOIs
StatePublished - Nov 14 2017

Keywords

  • DsbA-L
  • Inflammation
  • Insulin resistance
  • Obesity
  • cGAS

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway'. Together they form a unique fingerprint.

  • Cite this