EMBO Molecular Medicine (Mar 2015)
Defective NOD2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance
- Emmanuel Denou,
- Karine Lolmède,
- Lucile Garidou,
- Celine Pomie,
- Chantal Chabo,
- Trevor C Lau,
- Morgan D Fullerton,
- Giulia Nigro,
- Alexia Zakaroff‐Girard,
- Elodie Luche,
- Céline Garret,
- Matteo Serino,
- Jacques Amar,
- Michael Courtney,
- Joseph F Cavallari,
- Brandyn D Henriksbo,
- Nicole G Barra,
- Kevin P Foley,
- Joseph B McPhee,
- Brittany M Duggan,
- Hayley M O'Neill,
- Amanda J Lee,
- Philippe Sansonetti,
- Ali A Ashkar,
- Waliul I Khan,
- Michael G Surette,
- Anne Bouloumié,
- Gregory R Steinberg,
- Rémy Burcelin,
- Jonathan D Schertzer
Affiliations
- Emmanuel Denou
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Karine Lolmède
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Lucile Garidou
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Celine Pomie
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Chantal Chabo
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Trevor C Lau
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Morgan D Fullerton
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Giulia Nigro
- Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786 Institut Pasteur Paris France
- Alexia Zakaroff‐Girard
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Elodie Luche
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Céline Garret
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Matteo Serino
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Jacques Amar
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Michael Courtney
- VAIOMER SAS Prologue Biotech Labège France
- Joseph F Cavallari
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Brandyn D Henriksbo
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Nicole G Barra
- Department of Pathology and Molecular Medicine McMaster University Hamilton ON Canada
- Kevin P Foley
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Joseph B McPhee
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Brittany M Duggan
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- Hayley M O'Neill
- Department of Medicine McMaster University Hamilton ON Canada
- Amanda J Lee
- Department of Pathology and Molecular Medicine McMaster University Hamilton ON Canada
- Philippe Sansonetti
- Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786 Institut Pasteur Paris France
- Ali A Ashkar
- Department of Pathology and Molecular Medicine McMaster University Hamilton ON Canada
- Waliul I Khan
- Department of Pathology and Molecular Medicine McMaster University Hamilton ON Canada
- Michael G Surette
- Department of Medicine McMaster University Hamilton ON Canada
- Anne Bouloumié
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Gregory R Steinberg
- Department of Medicine McMaster University Hamilton ON Canada
- Rémy Burcelin
- Institut National de la Santé et de la Recherche Médicale (INSERM) Toulouse France
- Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences McMaster University Hamilton ON Canada
- DOI
- https://doi.org/10.15252/emmm.201404169
- Journal volume & issue
-
Vol. 7,
no. 3
pp. 259 – 274
Abstract
Abstract Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2−/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic‐derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2−/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN‐NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD‐fed NOD2−/− mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ‐free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.
Keywords