title: IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome.
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.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Department of Immunology, Monash University, Melbourne 3004, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kraakman
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
authors.forename: Helene L
authors.initials: HL
authors.lastname: Kammoun
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Department of Immunology, Monash University, Melbourne 3004, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Dragoljevic
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Department of Immunology, Monash University, Melbourne 3004, Australia.
authors.forename: Man K S
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.affiliation: Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Wentworth
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Motti
authors.initials: M
authors.lastname: Gerlic
authors.affiliation: Division of Systems Biology and Personalised Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Lachlan W
authors.initials: LW
authors.lastname: Whitehead
authors.affiliation: Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Ladina
authors.initials: L
authors.lastname: DiRago
authors.affiliation: Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Cengia
authors.affiliation: Division of ACRF Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lane
authors.affiliation: Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.affiliation: Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: Division of ACRF Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Division of Diabetes and Metabolism, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Electronic address: masters@wehi.edu.au.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight; D059305:Diet, High-Fat / Q000009:adverse effects; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000517:prevention & control; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D020382:Interleukin-18; C529636:NALP1 protein, mouse