AbstractHypermetabolism following severe burn injuries is associated with adipocyte dysfunction, elevated beige adipocyte formation, and increased energy expenditure. The resulting catabolism of adipose leads to detrimental sequelae such as fatty liver, increased risk of infections, sepsis, and even death. While the phenomenon of pathological white adipose tissue (WAT) browning is well‐documented in cachexia and burn models, the molecular mechanisms are essentially unknown. Here, we report that adipose triglyceride lipase (ATGL) plays a central role in burn‐induced WAT dysfunction and systemic outcomes. Targeting adipose‐specific ATGL in a murine (AKO) model resulted in diminished browning, decreased circulating fatty acids, and mitigation of burn‐induced hepatomegaly. To assess the clinical applicability of targeting ATGL, we demonstrate that the selective ATGL inhibitor atglistatin mimics the AKO results, suggesting a path forward for improving patient outcomes.
