The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity

The innate immune system oversees the response to danger signals. One of the most complexes organs that develops this response is the gut, which is extremely sensitive to the microbial changes in response to high saturated fat diets (HFD), leaving the space to be colonised by opportunistic bacteria, and triggering the innate immune response. Different evidence suggests the potential of the inflammasome in diet-induced inflammation, but little is known about its impact on the gut immunometabolic dysregulation. In this work, we report that the inflammasome adaptor apoptosis speck-like protein with a caspase activation domain (ASC) is essential for the development of obesity and insulin resistance during a high-fat diet (HFD). In ASC-deficient mice ( Pycard ^-/- ), lower weight gain and improved glucose tolerance were observed in comparison to wild type mice. Therefore, the absence of ASC reduces intestinal permeability and improves the benefitial effects of the gut microbiota, decreasing dysbiosis, making the intestinal environment healthier. Additionally, Pycard ^-/- mice presented an enhanced glycolysis and aerobic metabolism, contributing to reduced inflammation, fat accumulation in the liver and improved hepatic metabolic function. Developing therapies targeting ASC could be beneficial to treat obesity, type II diabetes, and metabolism-associated liver diseases.