Abstract
BACKGROUND: The complex interaction between the immune system and metabolic homeostasis is becoming recognized, as immune sensors affect key metabolic tissues, including the liver and adipose tissue. The cGAS-cGAMP-STING pathway, previously recognized as a cytosolic DNA-sensing pathway, is currently associated with lipid metabolism in addition to its inflammatory function. Although STING is acknowledged for its connection to cholesterol, the metabolic functions of its upstream component molecules-the DNA sensor cGAS and the resulting product cGAMP-are largely unexplored. We propose that cGAS and cGAMP serve as crucial, previously unidentified regulators of systemic lipid homeostasis throughout the lifetime. RESULTS: We investigated the long-term metabolic consequences of intrinsic cGAS deficiency, leading to the absence of cGAMP, in male mice fed on a standard chow diet. cGAS knockout (cGASKO) mice demonstrated a consistent increase in body weight across their lifespan, primarily attributed to adipocyte hypertrophy and increased adipose tissue mass. Increased weight correlated with elevated adiposity. This condition was associated with reduced weight-bearing strength, despite unchanged general locomotor activity and food intake during young age. Liver histology revealed modest cellular infiltration and absent steatosis, suggesting potential low-grade inflammation. Circulating triglyceride and glucose levels exhibited transient, age-dependent variations-decreased glucose and increased triglycerides in young age, which stabilized in adult and old ages, reflecting a possible compensatory metabolic adaptation with time. Conversely, total cholesterol levels were consistently and significantly elevated across all age groups, underscoring the importance of the cGAS-cGAMP axis in cholesterol homeostasis throughout life. CONCLUSIONS: Our study identified the cGAS-cGAMP axis as an interesting regulator of cholesterol homeostasis and fat accumulation in aging, independent of STING activation. The persistent deficiency of cGAS and cGAMP leads to lifelong hypercholesterolemia and adipose hypertrophy. This research highlights an unexpected metabolic function of the cGAS-cGAMP pathway and indicates the necessity of evaluating this axis in relation to physiological aging and metabolic disorders.