IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome Academic Article uri icon

abstract

  • 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.

authors

  • Murphy, Andrew J
  • Kraakman, Michael J
  • Kammoun, Helene L
  • Dragoljevic, Dragana
  • Lee, Man KS
  • Lawlor, Kate E
  • Wentworth, John M
  • Vasanthakumar, Ajithkumar
  • Gerlic, Motti
  • Whitehead, Lachlan W
  • DiRago, Ladina
  • Cengia, Louise
  • Lane, Rachael M
  • Metcalf, Donald
  • Vince, James E
  • Harrison, Leonard C
  • Kallies, Axel
  • Kile, Benjamin T
  • Croker, Ben A
  • Febbraio, Mark A
  • Masters, Seth L

publication date

  • January 2016