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

Publication date: Available online 20 April 2017
Source:Cell Metabolism
Author(s): Joseph F. Cavallari, Morgan D. Fullerton, Brittany M. Duggan, Kevin P. Foley, Emmanuel Denou, Brennan K. Smith, Eric M. Desjardins, Brandyn D. Henriksbo, Kalvin J. Kim, Brian R. Tuinema, Jennifer C. Stearns, David Prescott, Philip Rosenstiel, Brian K. Coombes, Gregory R. Steinberg, Jonathan D. Schertzer
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.

Graphical abstract

Teaser

Microbiota-derived components have been shown to promote inflammation and insulin resistance. Cavallari et al. show how a bacterial cell wall muropeptide acts via NOD2 as a "postbiotic" improving insulin resistance and metabolic tissue inflammation in obese mice, independently of weight loss or changes in microbiota composition.


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