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We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity\u2010promoting high\u2010fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\u2010derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN\u2010NOD2 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\u2010fed NOD2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ\u2010free 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.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404169","type":"journal-article","created":{"date-parts":[[2015,2,9]],"date-time":"2015-02-09T23:08:10Z","timestamp":1423523290000},"page":"259-274","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":198,"title":["Defective NOD2 peptidoglycan sensing promotes diet\u2010induced inflammation, dysbiosis, and insulin 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