Aims: Obesity is associated with immune cell infiltration and inflammation in metabolic tissues that contributes to insulin resistance. Pattern recognition receptors (PRRs) link obesity-induced inflammation and insulin resistance. Nucleotide oligomerization domain protein 2 (NOD2) is a PRR that detects muramyl dipeptide (MDP) present in the cell walls of all bacteria. NOD2 mutations are associated with inflammatory bowel disease, and NOD2 activation with MDP can ameliorate the inflammatory effects of experimental colitis in mice. Our lab has linked NOD2 immunity with metabolism and found that NOD2 deficiency exacerbates obesity-induced inflammation and insulin resistance. We sought to determine if NOD2 activation with MDP confers anti-inflammatory effects during acute bacterial or chronic dietary stress. We have found that MDP has anti-inflammatory and insulin sensitizing effects in mice during bacterial stress and diet-induced obesity.

Methods: Mice were fed a chow or high fat diet (HFD; 60% kcal from fat) for 5 weeks. MDP (100 ug) or LPS (0.2 mg/kg) was administered i.p. as indicated. Glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamps were performed in 6h-fasted conscious mice. Tissues were immediately collected and frozen in liquid nitrogen. Gene expression was determined by RT-PCR with TaqMan assays.

Results: Mice that received MDP prior to LPS challenge had increased glucose tolerance, reduced glucose-stimulated insulin secretion, and increased suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamps. Mice that received MDP throughout a HFD were more glucose and insulin tolerant, experienced less hepatic insulin resistance during clamps, and had lower expression of many inflammatory markers in adipose and liver tissues.

Conclusions: NOD2 activation improves glucose homeostasis during acute bacterial stress and reduces inflammation and metabolic defects associated with diet-induced obesity.