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.
Highlights
Obesity is a global epidemic that is caused by excessive energy intake or inefficient energy expenditure
We previously found that in addition to increased chronic sterile inflammation and exacerbated insulin resistance, the fat-specific disulfide bond A oxidoreductase-like protein (DsbA-L) knockout mice (DsbA-LfKO) displayed increased susceptibility to high-fat diet (HFD)-induced obesity compared with the loxp littermates
Given that fat-specific knockout of DsbA-L had no effect on food intake[5] and physical activity (Fig. 1a), we postulated that the increased body weight and adiposity in the DsbALfKO mice might be due to decreased thermogenesis and energy expenditure
Summary
Obesity is a global epidemic that is caused by excessive energy intake or inefficient energy expenditure. Several studies showed that in addition to being activated by pathogen-derived DNAs from viral or microbial infection, the cGAS–STING pathway could be initiated by self-DNAs such as mitochondrial DNAs (mtDNAs) aberrantly localized in the cytosol under certain stress conditions[2,3,4,5] This finding suggests broad functions of the innate immune pathway in mitochondrial enriched tissues or cells. We show that cytosolic mtDNA-induced activation of the cGAS–STING pathway functions as a key sentinel signaling to suppress thermogenic fuel influx and gene expression in adipose tissue of the DsbA-LfKO mice. Our study uncovers a link of mitochondrial dysfunction-derived immune response to thermogenesis and energy expenditure in adipose tissue, suggesting the cGAS–STING pathway may be an effective therapeutic target for the treatment of obesity and its associated diseases
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