High-fat diet-induced loss of muramyl dipeptide sensitivity

Abstract

Glucagon-like peptide-1 (GLP-1) is an insulin-stimulating hormone released from enteroendocrine cells. Muramyl dipeptide (MDP) is a peptidoglycan motif which has insulin- sensitizing effects in obesogenic mice by acting through the nucleotide oligomerization domain 2 (NOD2) receptor. We hypothesized that MDP enhances glucose tolerance by inducing intestinal GLP-1 secretion through NOD2 activation. We observed a significant increase in GLP-1 secretion when L-cells were treated with a fatty acid MDP derivative (L18-MDP). Additionally, we demonstrated NOD2 expression in mouse intestine and in L-cells. Two intraperitoneal injections of MDP (5mg/kg) significantly increased fasting total GLP-1 in chow-fed mice; an effect that was lost during the onset of hyperglycemia during a high-fat diet. No improvement in oral glucose tolerance was observed in MDP-treated mice. Finally, we demonstrated in L-cells that hyperglycemic conditions reduce NOD2 and GLP-1 mRNA expression. Together these findings suggest MDP may play a role in enhancing GLP-1 during euglycemia but loses its ability to do so in hyperglycemia.