Interleukin-18 (IL-18) is activated by caspase-1 in inflammasome complexes and has anti-obesity effects. We have recently discovered that the NLRP1 inflammasome is the major driver of IL-18 production in obesity. Mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not when mice are fed a HFD with low energy density (high fibre). Furthermore, mice with an activating mutation in NLRP1, and hence increased IL-18, have decreased adiposity and are resistant to diet-induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Thus, we have discovered that NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome. We are now exploring how the NLRP1 inflammasome in activated in the setting of metabolic stress and further exploring the anti-obesity mechanisms of IL-18 with a focus on lipolysis.