TY - JOUR
T1 - Mitochondrial stress-activated cGAS-STING pathway inhibits thermogenic program and contributes to overnutrition-induced obesity in mice
AU - Bai, Juli
AU - Cervantes, Christopher
AU - He, Sijia
AU - He, Jieyu
AU - Plasko, George R.
AU - Wen, Jie
AU - Li, Zhi
AU - Yin, Dongqing
AU - Zhang, Chuntao
AU - Liu, Meilian
AU - Dong, Lily Q.
AU - Liu, Feng
N1 - Funding Information:
We are grateful to Dr Jiandie Lin (Life Sciences Institute, University of Michigan) for his generous gift of brown adipocyte cell line. We also thank Dr Elizabeth Fernandez (Department of Pharmacology and Barshop Institute for Longevity and Aging Studies, UTHSA) for her kind help with the metabolic cage study. We also thank the efforts of the UTHSA institutional Mass Spectrometry Laboratory and support from NIH grant P30 CA54174. We also thank the support from Biobanking & Genome Analysis Core of UTHSA for real-time PCR experiment. This work was supported in part by NIH R01 grants DK114479, DK115761, and DK102965, Innovative Basic Science Awards of American Diabetes Association 1-19-IBS-147, and grants from the National Natural Science Foundation of China 81730022 and 81870601.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-020-0986-1
DO - 10.1038/s42003-020-0986-1
M3 - Article
C2 - 32444826
AN - SCOPUS:85085263579
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 257
ER -