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

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 46; pp. 12196 - 12201
Main Authors Bai, Juli, Cervantes, Christopher, Liu, Juan, He, Sijia, Zhou, Haiyan, Zhang, Bilin, Cai, Huan, Yin, Dongqing, Hu, Derong, Li, Zhi, Chen, Hongzhi, Gao, Xiaoli, Wang, Fang, O’Connor, Jason C., Xu, Yong, Liu, Meilian, Dong, Lily Q., Liu, Feng
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 14.11.2017
Subjects
Activation
Adipose tissue
Biological Sciences
Cytosol
Deoxyribonucleic acid
DNA
High fat diet
Immunosurveillance
Inflammation
Insulin
Insulin resistance
Mitochondria
Mitochondrial DNA
Obesity
Oxidoreductase
Proteins
cGAS
inflammation
insulin resistance
DsbA-L
obesity
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ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1708744114

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Summary: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.
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Author contributions: J.B. and F.L. designed research; J.B., C.C., J.L., S.H., H.Z., B.Z., H. Cai, D.Y., D.H., Z.L., H. Chen, X.G., F.W., J.C.O., Y.X., and M.L. performed research; J.B., C.C., J.L., H.Z., H. Cai, X.G., J.C.O., and F.L. analyzed data; and J.B., L.Q.D., and F.L. wrote the paper.
Edited by Alan Saltiel, University of California, San Diego, La Jolla, CA, and accepted by Editorial Board Member David J. Mangelsdorf October 4, 2017 (received for review May 26, 2017)
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1708744114