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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