Defective <scp>NOD</scp>2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance

<jats:title>Abstract</jats:title><jats:p>Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that <jats:styled-content style="fixed-case">NOD</jats:styled-content>2 detection of bacterial cell wall peptidoglycan (<jats:styled-content style="fixed-case">PGN</jats:styled-content>) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet (<jats:styled-content style="fixed-case">HFD</jats:styled-content>) increased <jats:styled-content style="fixed-case">NOD</jats:styled-content>2 in hepatocytes and adipocytes, and <jats:styled-content style="fixed-case">NOD</jats:styled-content>2<jats:sup>−/−</jats:sup> mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a <jats:styled-content style="fixed-case">HFD</jats:styled-content>. This effect is independent of altered adiposity or <jats:styled-content style="fixed-case">NOD</jats:styled-content>2 in hematopoietic‐derived immune cells. Instead, increased metabolic inflammation and insulin resistance in <jats:styled-content style="fixed-case">NOD</jats:styled-content>2<jats:sup>−/−</jats:sup> mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact <jats:styled-content style="fixed-case">PGN</jats:styled-content>‐<jats:styled-content style="fixed-case">NOD</jats:styled-content>2 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 <jats:styled-content style="fixed-case">HFD</jats:styled-content>‐fed <jats:styled-content style="fixed-case">NOD</jats:styled-content>2<jats:sup>−/−</jats:sup> mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to <jats:styled-content style="fixed-case">WT</jats:styled-content>, 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.</jats:p>