Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4

Cell Metab. 2017 May 2;25(5):1063-1074.e3. doi: 10.1016/j.cmet.2017.03.021. Epub 2017 Apr 20.


Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome. MDP reduced hepatic insulin resistance during obesity and low-level endotoxemia. NOD1-activating muropeptides worsened glucose tolerance. IRF4 distinguished opposing glycemic responses to different types of peptidoglycan and was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia. IRF4 was dispensable for exacerbated glucose intolerance via NOD1. Mifamurtide, an MDP-based drug with orphan drug status, was an insulin sensitizer at clinically relevant doses in obese mice.

Keywords: diabetes; endotoxemia; glucose; inflammation; insulin resistance; microbiome; microbiota; obesity; peptidoglycan.

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / immunology*
  • Animals
  • Endotoxemia / complications
  • Endotoxemia / immunology
  • Endotoxemia / microbiology
  • Inflammation / complications
  • Inflammation / immunology
  • Inflammation / microbiology
  • Insulin Resistance*
  • Interferon Regulatory Factors / immunology*
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microbiota
  • Nod1 Signaling Adaptor Protein / immunology
  • Nod2 Signaling Adaptor Protein / immunology
  • Obesity / complications*
  • Obesity / immunology
  • Obesity / microbiology*


  • Interferon Regulatory Factors
  • Nod1 Signaling Adaptor Protein
  • Nod1 protein, mouse
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • interferon regulatory factor-4
  • Acetylmuramyl-Alanyl-Isoglutamine