TY - JOUR
T1 - IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome
AU - Murphy, Andrew J.
AU - Kraakman, Michael J.
AU - Kammoun, Helene L.
AU - Dragoljevic, Dragana
AU - Lee, Man K.S.
AU - Lawlor, Kate E.
AU - Wentworth, John M.
AU - Vasanthakumar, Ajithkumar
AU - Gerlic, Motti
AU - Whitehead, Lachlan W.
AU - Dirago, Ladina
AU - Cengia, Louise
AU - Lane, Rachael M.
AU - Metcalf, Donald
AU - Vince, James E.
AU - Harrison, Leonard C.
AU - Kallies, Axel
AU - Kile, Benjamin T.
AU - Croker, Ben A.
AU - Febbraio, Mark A.
AU - Masters, Seth L.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84955295531&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2015.09.024
DO - 10.1016/j.cmet.2015.09.024
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C2 - 26603191
AN - SCOPUS:84955295531
SN - 1550-4131
VL - 23
SP - 155
EP - 164
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -
