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 (PPARalpha). 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 PPARalpha. PPARalpha immunoreactivity was examined in whole mount preparations of mouse gastrointestinal (GI) tract. The effect of OEA on motility was assessed in wildtype, PPARalpha, cannabinoid CB(1) receptor and CB(2) 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 PPARalpha antagonist GW6471, transient receptor potential vanilloid 1 antagonist SB366791 or the glucagon-like peptide 1 antagonist exendin-3(9-39) amide. PPARalpha 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 PPARalpha, CB(1) and CB(2) receptor gene-deficient mice and in the presence of GW6471, SB366791 and exendin-3(9-39) amide, suggesting neither PPARalpha 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 PPARalpha is found in the enteric nervous system, but our results suggest that PPARalpha is not involved in the suppression of motility by OEA.
Cluny
N L
NL
Department of Physiology and Biophysics, Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, AB, Canada.
Keenan
C M
CM
Lutz
B
B
Piomelli
D
D
Sharkey
K A
KA
D000818:Animals; D063388:Endocannabinoids; D005769:Gastrointestinal Motility / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009829:Oleic Acids / Q000378:metabolism*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000235:genetics; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors
D063388:Endocannabinoids; D009829:Oleic Acids; D047493:PPAR alpha; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C488250:oleoylethanolamide; D052216:Glucagon-Like Peptide 1