IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome

•Deletion of NLRP1 in mice leads to obesity and metabolic syndrome•NLRP1 obesity phenotype is related to the energy quotient of the diet•Loss of NLRP1 decreased IL-18 production and lipolysis•NLRP1 activation increased IL-18, prevented obesity, but was fatal on the high-fat diet

SummaryInterleukin-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.

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