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Cell Metab. 2016 Jan 12;23(1):155-64. doi: 10.1016/j.cmet.2015.09.024. Epub 2015 Oct 22.

IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome.

Author information

1
Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia; Department of Immunology, Monash University, Melbourne 3004, Australia.
2
Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
3
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.
4
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.
5
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.
6
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.
7
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
8
Division of Systems Biology and Personalised Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
9
Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
10
Division of ACRF Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
11
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.
12
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.
13
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
14
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.
15
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.

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.

PMID:
26603191
DOI:
10.1016/j.cmet.2015.09.024
[Indexed for MEDLINE]
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