INHIBITION OF FOOD-INTAKE BY NEUROPEPTIDE-Y Y5 RECEPTOR ANTISENSE OLIGODEOXYNUCLEOTIDES

The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subt ype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. Thes e conclusions were based on studies with peptidic agonists. We now rep ort studies in which phosphothioate end-protected antisense oligodeoxy nucleotides (ODNs) targeted to prepro NPY (prepro NPY antisense ODNs) or to the Y5 receptor (Y5 antisense ODNs) were used to assess the func tional importance of this novel receptor subtype in vivo. NPY antisens e ODNs given intracerebroventricularly to rats prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasti ng-induced food intake. Likewise, repeated intracerebroventricular inj ections of Y5 antisense ODNs prevented fasting-induced food intake in rats. Moreover, two Y5 antisense ODNs, targeted to different sequences of the receptor, significantly decreased basal food intake and inhibi ted the increase in food intake after intracerebroventricular injectio n of NPY. These effects proved to be selective, since the feeding resp onse to galanin was not affected. Analysis of the structure of feeding behavior revealed that prepro NPY and Y5 receptor antisense ODNs redu ced food intake by inducing decreases in meal size and meal duration a nalogous to the orexigenic effects of NPY that are mediated by increas es in these parameters. Although changes in Y5 receptor density could not be measured, the results with Y5 antisense ODNs strongly suggest t hat this receptor subtype mediates the feeding response to exogenous a nd endogenous NPY. Selective Y5 antagonists may therefore be of therap eutic value for the treatment of obesity and eating disorders.