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.
|ISBN||1932-7420 (Electronic) 1550-4131 (Linking)|
|Authors||Murphy, A. J.; Kraakman, M. J.; Kammoun, H. L.; Dragoljevic, D.; Lee, M. K.; Lawlor, K. E.; Wentworth, J. M.; Vasanthakumar, A.; Gerlic, M.; Whitehead, L. W.; DiRago, L.; Cengia, L.; Lane, R. M.; Metcalf, D.; Vince, J. E.; Harrison, L. C.; Kallies, A.; Kile, B. T.; Croker, B. A.; Febbraio, M. A.; Masters, S. L.;|
|Publisher Name||Cell Metabolism|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26603191|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13601|