Defective NOD 2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance Academic Article uri icon

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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

  • Denou, Emmanuel
  • Lolmède, Karine
  • Garidou, Lucile
  • Pomie, Celine
  • Chabo, Chantal
  • Lau, Trevor C
  • Fullerton, Morgan D
  • Nigro, Giulia
  • Zakaroff‐Girard, Alexia
  • Luche, Elodie
  • Garret, Céline
  • Serino, Matteo
  • Amar, Jacques
  • Courtney, Michael
  • Cavallari, Joseph F
  • Henriksbo, Brandyn D
  • Barra, Nicole G
  • Foley, Kevin P
  • McPhee, Joseph B
  • Duggan, Brittany M
  • O'Neill, Hayley M
  • Lee, Amanda J
  • Sansonetti, Philippe
  • Ashkar, Ali A
  • Khan, Waliul
  • Surette, Michael
  • Bouloumié, Anne
  • Steinberg, Gregory
  • Burcelin, Rémy
  • Schertzer, Jonathan

publication date

  • March 2015