IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome

Andrew J. Murphy, Michael J. Kraakman, Helene L. Kammoun, Dragana Dragoljevic, Man K.S. Lee, Kate E. Lawlor, John M. Wentworth, Ajithkumarx Vasanthakumar, Motti Gerlic, Lachlan W Whitehead, Ladina DiRago, Louise Cengia, Rachael M Lane, Donald Metcalf, James E. Vince, Leonard C. Harrison, Axel Kallies, Benjamin T. Kile, Ben A Croker, Mark A. Febbraio & 1 others Seth L. Masters

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)155-164
Number of pages10
JournalCell Metabolism
Volume23
Issue number1
DOIs
Publication statusPublished - 12 Jan 2016

Cite this

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. / IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. In: Cell Metabolism. 2016 ; Vol. 23, No. 1. pp. 155-164.
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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.",
author = "Murphy, {Andrew J.} and Kraakman, {Michael J.} and Kammoun, {Helene L.} and Dragana Dragoljevic and Lee, {Man K.S.} and Lawlor, {Kate E.} and Wentworth, {John M.} and Ajithkumarx Vasanthakumar and Motti Gerlic and Whitehead, {Lachlan W} and Ladina DiRago and Louise Cengia and Lane, {Rachael M} and Donald Metcalf and Vince, {James E.} and Harrison, {Leonard C.} and Axel Kallies and Kile, {Benjamin T.} and Croker, {Ben A} and Febbraio, {Mark A.} and Masters, {Seth L.}",
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Murphy, AJ, Kraakman, MJ, Kammoun, HL, Dragoljevic, D, Lee, MKS, Lawlor, KE, Wentworth, JM, Vasanthakumar, A, Gerlic, M, Whitehead, LW, DiRago, L, Cengia, L, Lane, RM, Metcalf, D, Vince, JE, Harrison, LC, Kallies, A, Kile, BT, Croker, BA, Febbraio, MA & Masters, SL 2016, 'IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome' Cell Metabolism, vol. 23, no. 1, pp. 155-164. https://doi.org/10.1016/j.cmet.2015.09.024

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 journalArticleResearchpeer-review

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AU - Vince, James E.

AU - Harrison, Leonard C.

AU - Kallies, Axel

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AU - Masters, Seth L.

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