Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways.
Oleylethanolamide (OEA) is a lipid mediator that inhibits food intake and body weight gain and also exhibits hypolipemiant actions. OEA exerts its anorectic effects peripherally through the stimulation of C-fibers. OEA is synthesized in the intestine in response to feeding, increasing its levels in portal blood after the meal. Moreover, OEA is produced by adipose tissue, and a lipolytic effect has been found. In this work, we have examined the effect of OEA on glucose metabolism in rats in vivo and in isolated adipocytes. In vivo studies showed that acute administration (30 min and 6 h) of OEA produced glucose intolerance without decreasing insulin levels. Ex vivo, we found that 10 min of preincubation with OEA inhibited 30% insulin-stimulated glucose uptake in isolated adipocytes. Maximal effect was achieved at 1 microM OEA. The related compounds palmitylethanolamide and oleic acid had no effect, suggesting a specific mechanism. Insulin-stimulated GLUT4 translocation was not affected, but OEA promoted Ser/Thr phosphorylation of GLUT4, which may impair transport activity. This phosphorylation may be partly mediated by p38 and JNK kinases, since specific inhibitors (SB-203580 and SP-600125) partly reverted the inhibitory effect of OEA on insulin-stimulated glucose uptake. These results suggest that the lipid mediator OEA inhibits insulin action in the adipocyte, impairing glucose uptake via p38 and JNK kinases, and these effects may at least in part explain the glucose intolerance produced in rats in vivo. These effects of OEA may contribute to the anorectic effects induced by this mediator, and they might be also relevant for insulin resistance in adipose tissue.
González-Yanes
Carmen
C
Dept. of Medical Biochemistry and Molecular Biology, School of Medicine, Investigation Unit, Virgen Macarena Univ. Hospital, Av. Sanchez Pizjuan 4, Seville 41009, Spain.
Serrano
Antonia
A
Bermúdez-Silva
Francisco Javier
FJ
Hernández-Dominguez
María
M
Páez-Ochoa
María Angeles
MA
Rodríguez de Fonseca
Fernando
F
Sánchez-Margalet
Víctor
V
D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009829:Oleic Acids / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D009829:Oleic Acids; C440229:Oleylethanolamide; C495694:Slc2a4 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose