DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway.
Juli BaiChristopher CervantesJuan LiuSijia HeHaiyan ZhouBilin ZhangHuan CaiDongqing YinDerong HuZhi LiHongzhi ChenXiaoli GaoFang WangJason C O'ConnorYong XuMeilian LiuLily Q DongFeng LiuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
- insulin resistance
- high fat diet induced
- adipose tissue
- oxidative stress
- diabetic rats
- metabolic syndrome
- high fat diet
- skeletal muscle
- polycystic ovary syndrome
- type diabetes
- high glucose
- weight loss
- drug induced
- signaling pathway
- innate immune
- cell proliferation
- glycemic control
- transcription factor
- public health
- gene expression
- single molecule
- dna methylation
- cell free
- genome wide
- body mass index