The identification of peroxisome proliferator-activated receptor alpha-independent effects of oleoylethanolamide on intestinal transit in mice

Oleoylethanolamide (OEA) is an endogenous lipid produced in the intestine that mediates satiety by activation of peroxisome proliferator-activated receptor alpha (PPAR alpha). OEA inhibits gastric emptying and intestinal motility, but the mechanism of action remains to be determined. We investigated whether OEA inhibits intestinal motility by activation of PPAR alpha. PPAR alpha immunoreactivity was examined in whole mount preparations of mouse gastrointestinal (GI) tract. The effect of OEA on motility was assessed in wildtype, PPAR alpha, cannabinoid CB1 receptor and CB2 receptor gene-deficient mice and in a model of accelerated GI transit. In addition, the effect of OEA on motility was assessed in mice injected with the PPAR alpha antagonist GW6471, transient receptor potential vanilloid 1 antagonist SB366791 or the glucagon-like peptide 1 antagonist exendin-3(9-39) amide. PPAR alpha immunoreactivity was present in neurons in the myenteric and submucosal plexuses throughout the GI tract. OEA inhibited upper GI transit in a dose-dependent manner, but was devoid of an effect on whole gut transit or colonic propulsion. OEA-induced inhibition of motility was still present in PPAR alpha, CB1 and CB2 receptor gene-deficient mice and in the presence of GW6471, SB366791 and exendin-3(9-39) amide, suggesting neither PPAR alpha nor the cannabinoids and other likely receptors are involved in mediating the effects of OEA. OEA blocked stress-induced accelerated upper GI transit at a dose that had no effect on physiological transit. We show that PPAR alpha is found in the enteric nervous system, but our results suggest that PPAR alpha is not involved in the suppression of motility by OEA.