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.
| Original language | English |
|---|---|
| Pages (from-to) | 155-164 |
| Number of pages | 10 |
| Journal | Cell Metabolism |
| Volume | 23 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 12 Jan 2016 |
Cite this
}
IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. / Murphy, Andrew J.; Kraakman, Michael J.; Kammoun, Helene L.; Dragoljevic, Dragana; Lee, Man K.S.; Lawlor, Kate E.; Wentworth, John M. ; Vasanthakumar, Ajithkumarx; 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.
In: Cell Metabolism, Vol. 23, No. 1, 12.01.2016, p. 155-164.Research output: Contribution to journal › Article › Research › peer-review
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, Ajithkumarx
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.
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
M3 - Article
VL - 23
SP - 155
EP - 164
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -