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

Author
item BAI, JULI - UNIVERSITY OF TEXAS AT SAN ANTONIO
item CERVANTES, CHRISTOPHER - UNIVERSITY OF TEXAS AT SAN ANTONIO
item LIU, JUAN - UNIVERSITY OF TEXAS AT SAN ANTONIO
item HE, SIJIA - UNIVERSITY OF TEXAS AT SAN ANTONIO
item ZHOU, HAIYAN - CENTRAL SOUTH UNIVERSITY
item ZHANG, BILIN - UNIVERSITY OF TEXAS AT SAN ANTONIO
item CAI, HUAN - UNIVERSITY OF TEXAS AT SAN ANTONIO
item YIN, DONGQING - UNIVERSITY OF TEXAS AT SAN ANTONIO
item HU, DERONG - UNIVERSITY OF TEXAS AT SAN ANTONIO
item LI, ZHI - UNIVERSITY OF TEXAS AT SAN ANTONIO
item CHEN, HONGZHI - UNIVERSITY OF TEXAS AT SAN ANTONIO
item GAO, XIAOLI - UNIVERSITY OF TEXAS AT SAN ANTONIO
item O'CONNOR, JASON - UNIVERSITY OF TEXAS AT SAN ANTONIO
item XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LIU, MEILIAN - UNIVERSITY OF NEW MEXICO
item DONG, LILY - UNIVERSITY OF TEXAS AT SAN ANTONIO
item LIU, FENG - UNIVERSITY OF TEXAS AT SAN ANTONIO

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/4/2017
Publication Date: 11/14/2017
Citation: Bai, J., Cervantes, C., Liu, J., He, S., Zhou, H., Zhang, B., Cai, H., Yin, D., Hu, D., Li, Z., Chen, H., Gao, X., O'Connor, J., Xu, Y., Liu, M., Dong, L., Liu, F. 2017. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proceedings of the National Academy of Sciences. 114(46):12196-12201.

Interpretive Summary: Obesity and associated metabolic dysfunctions constitute a serious global health problem. Here we showed that DsbA-L, a molecule in cells, can prevent inflammation and metabolic dysfunctions evoked by obesity. These findings suggested that DsbA-L could be a potential target for treatment of obesity and diabetes.

Technical 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 cGAScGAMP-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.