Submitted on November 19, 2004
Accepted on April 28, 2005
Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways
Carmen Gonzalez-Yanes1, Antonia Serrano2, Francisco Javier Bermudez-Silva2, Maria Hernandez-Dominguez1, Maria Angeles Paez-Ochoa1, Fernando Rodriguez de Fonseca2, and Victor Sanchez-Margalet1*
1 Medical Biochemistry and Molecular Biology, Investigation Unit, Virgen Macarena University Hospital, School of Medicine, University of Seville, Seville, Spain
2 Investigation Unit, Hospital Carlos Haya, Fundacion IMABIS, Malaga, Spain
* To whom correspondence should be addressed. E-mail: margalet{at}us.es.
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 the 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) OEA produced glucose intolerance, without decreasing insulin levels. Ex vivo, we found that 10 min preincubation with OEA inhibited 30% insulin stimulated glucose uptake in isolated adipocytes. Maximal effect was achieved at 1 micromolar OEA. The related compounds palmitylethanolamide and oleic acid had no effect suggesting a specific mechanism. Insulin-stimulated GLUT-4 translocation was not affected, but OEA promoted Ser/Thr phosphorylation of GLUT-4, which may impair transport activity. This phosphorylation may be partly mediated by p38 and JNK kinases since specific inhibitors (SB203580 and SP600125) 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 anorexic effects induced by this mediator, and they might be also relevant for insulin resistance in adipose tissue.
