IL 18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome.
Interleukin 18 (IL 18) is activated by Caspase 1 in inflammasome complexes and has anti obesity effects; however, it is not known which inflammasome regulates this process. We found that 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 fiber) 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, NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL 18, preventing obesity and metabolic syndrome.
Cell metabolism