Format

Send to

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

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

Author information

1
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
2
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
3
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
4
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Institute of Clinical Molecular Biology (IKMB), University of Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany.
6
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada.
7
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
8
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: schertze@mcmaster.ca.

Abstract

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

PMID:
28434881
DOI:
10.1016/j.cmet.2017.03.021
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center