Defective NOD 2 peptidoglycan sensing promotes diet‐induced inflammation, dysbiosis, and insulin resistance

Abstract

Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that NOD 2 detection of bacterial cell wall peptidoglycan ( PGN ) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet ( HFD ) increased NOD 2 in hepatocytes and adipocytes, and NOD 2 −/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD . This effect is independent of altered adiposity or NOD 2 in hematopoietic‐derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD 2 −/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN ‐ NOD 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 HFD ‐fed NOD 2 −/− 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. image Nutritional and bacterial cues engage the immune system during the chronic inflammation associated with obesity, which could lead to insulin resistance. An intact NOD 2‐peptidoglycan sensing system prevents excessive dysbiosis‐related inflammation and insulin resistance during obesity. NOD 2 in non‐hematopoietic cells protects against obesity‐induced inflammation and insulin resistance. NOD 2 limits accumulation of bacterial markers and inflammation of adipose and liver tissues during obesity. The microbiota of NOD 2‐deficient mice contributes to metabolic inflammation and insulin resistance.