title: Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance.
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.
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Emmanuel
authors: E
authors: Denou
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France.
authors: Karine
authors: K
authors: Lolmède
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Lucile
authors: L
authors: Garidou
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Celine
authors: C
authors: Pomie
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France VAIOMER SAS, Prologue Biotech, Labège, France.
authors: Chantal
authors: C
authors: Chabo
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Trevor C
authors: TC
authors: Lau
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors: Morgan D
authors: MD
authors: Fullerton
authors: Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786 Institut Pasteur, Paris, France.
authors: Giulia
authors: G
authors: Nigro
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France.
authors: Alexia
authors: A
authors: Zakaroff-Girard
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Elodie
authors: E
authors: Luche
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Céline
authors: C
authors: Garret
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Matteo
authors: M
authors: Serino
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France.
authors: Jacques
authors: J
authors: Amar
authors: VAIOMER SAS, Prologue Biotech, Labège, France.
authors: Michael
authors: M
authors: Courtney
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Joseph F
authors: JF
authors: Cavallari
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Brandyn D
authors: BD
authors: Henriksbo
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors: Nicole G
authors: NG
authors: Barra
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Kevin P
authors: KP
authors: Foley
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Joseph B
authors: JB
authors: McPhee
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors: Brittany M
authors: BM
authors: Duggan
authors: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors: Hayley M
authors: HM
authors: O'Neill
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors: Amanda J
authors: AJ
authors: Lee
authors: Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786 Institut Pasteur, Paris, France.
authors: Philippe
authors: P
authors: Sansonetti
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors: Ali A
authors: AA
authors: Ashkar
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute McMaster University, Hamilton, ON, Canada.
authors: Waliul I
authors: WI
authors: Khan
authors: Department of Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute McMaster University, Hamilton, ON, Canada.
authors: Michael G
authors: MG
authors: Surette
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 1: «stroma-vascular cells of adipose tissue», Toulouse, France.
authors: Anne
authors: A
authors: Bouloumié
authors: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors: Gregory R
authors: GR
authors: Steinberg
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France Université Paul Sabatier (UPS) Unité Mixte de Recherche (UMR) 1048 Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) Team 2: «Intestinal Risk Factors, Diabetes, Dyslipidemia», Toulouse Cedex 4, France remy.burcelin@inserm.fr schertze@mcmaster.ca.
authors: Rémy
authors: R
authors: Burcelin
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada remy.burcelin@inserm.fr schertze@mcmaster.ca.
authors: Jonathan D
authors: JD
authors: Schertzer
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D002473:Cell Wall / Q000737:chemistry; D004032:Diet / Q000379:methods*; D064806:Dysbiosis; D007249:Inflammation / Q000473:pathology*; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D010457:Peptidoglycan / Q000032:analysis / Q000378:metabolism*
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan
keywords: diabetes; glucose; metabolic inflammation; microbiome; obesity