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- Title
Mitochondrial stress-activated cGAS-STING pathway inhibits thermogenic program and contributes to overnutrition-induced obesity in mice.
- Authors
Bai, Juli; Cervantes, Christopher; He, Sijia; He, Jieyu; Plasko, George R.; Wen, Jie; Li, Zhi; Yin, Dongqing; Zhang, Chuntao; Liu, Meilian; Dong, Lily Q.; Liu, Feng
- Abstract
Obesity is a global epidemic that is caused by excessive energy intake or inefficient energy expenditure. Brown or beige fat dissipates energy as heat through non-shivering thermogenesis by their high density of mitochondria. However, how the mitochondrial stress-induced signal is coupled to the cellular thermogenic program remains elusive. Here, we show that mitochondrial DNA escape-induced activation of the cGAS-STING pathway negatively regulates thermogenesis in fat-specific DsbA-L knockout mice, a model of adipose tissue mitochondrial stress. Conversely, fat-specific overexpression of DsbA-L or knockout of STING protects mice against high-fat diet-induced obesity. Mechanistically, activation of the cGAS-STING pathway in adipocytes activated phosphodiesterase PDE3B/PDE4, leading to decreased cAMP levels and PKA signaling, thus reduced thermogenesis. Our study demonstrates that mitochondrial stress-activated cGAS-STING pathway functions as a sentinel signal that suppresses thermogenesis in adipose tissue. Targeting adipose cGAS-STING pathway may thus be a potential therapeutic strategy to counteract overnutrition-induced obesity and its associated metabolic diseases. Juli Bai et al. demonstrate that overexpression of DsbA-L or knockout of STING in adipocytes protects mice against high-fat diet-induced obesity. They find that inhibition of the cGAS-STING pathway in adipocytes activates thermogenesis. This study presents the cGAS-STING pathway as a potential target for anti-obesity therapeutics.
- Subjects
OBESITY; BODY temperature regulation; PHOSPHODIESTERASES; FAT cells; MITOCHONDRIAL DNA
- Publication
Communications Biology, 2020, Vol 3, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-020-0986-1