The inflammasome adaptor protein ASC present differential intracellular and extracellular functions to trigger immunometabolic dysregulation and dysbiosis during obesity.

BACKGROUND: High-fat diets activate intestinal inflammasomes, promoting dysbiosis, metabolic dysfunction, and inflammation. The apoptosis speck-like protein with a caspase activation domain (ASC) is a key adaptor for inflammasome activation, but its role in diet-induced metabolic alterations remains unclear. METHODS: We investigated the metabolic and inflammatory consequences of ASC deficiency using Pycard-/- mice fed a high-fat diet. Body weight, glucose tolerance, intestinal and hepatic metabolic profiles, and inflammatory markers were assessed. To evaluate extracellular ASC function, ASC oligomers were administered to Pycard-/- mice. RESULTS: ASC-deficient mice displayed reduced weight gain and improved glucose tolerance compared with wild-type controls. Pycard-/- mice also showed enhanced intestinal and hepatic metabolic profiles and decreased inflammation. Extracellular administration of ASC oligomers partially restored dysbiosis, intestinal metabolic changes, and inflammatory responses in Pycard-/- mice. CONCLUSIONS: ASC contributes to metabolic dysregulation through both its canonical intracellular role in inflammasome activation and an extracellular oligomer-mediated mechanism. These findings identify ASC as a relevant target for interventions aimed at improving obesity-associated metabolic and inflammatory disturbances.