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EMBO Mol Med. 2015 Mar;7(3):259-74. doi: 10.15252/emmm.201404169.

Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance.

Author information

1
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
2
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.
3
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.
4
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.
5
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada Department of Medicine, McMaster University, Hamilton, ON, Canada.
6
Unité de Pathogénie Microbienne Moléculaire and Unité INSERM 786 Institut Pasteur, Paris, France.
7
VAIOMER SAS, Prologue Biotech, Labège, France.
8
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
9
Department of Medicine, McMaster University, Hamilton, ON, Canada.
10
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute McMaster University, Hamilton, ON, Canada.
11
Department of Medicine, McMaster University, Hamilton, ON, Canada Farncombe Family Digestive Health Research Institute McMaster University, Hamilton, ON, Canada.
12
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.
13
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada remy.burcelin@inserm.fr schertze@mcmaster.ca.

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:

diabetes; glucose; metabolic inflammation; microbiome; obesity

PMID:
25666722
PMCID:
PMC4364944
DOI:
10.15252/emmm.201404169
[Indexed for MEDLINE]
Free PMC Article

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