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 DugganHayley 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

Research output: Contribution to journalArticleResearchpeer-review

92 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)259-274
Number of pages16
JournalEMBO Molecular Medicine
Volume7
Issue number3
DOIs
Publication statusPublished - 9 Feb 2015
Externally publishedYes

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