Activation of central neuropeptide YY1 receptors potently stimulates food intake in male rhesus monkeys

The orexigenic role of central neuropeptide Y (NPY) in nonhuman primates has been questioned. Therefore, we have studied the effect of central NPY on feeding in ad libitum-fed male rhesus macaques. NPY dose-dependently increased food intake, with the maximal effect obtained by 50 mu g (960 min food intake +/- SEM, 104 +/- 5 to 188 +/- 11 g; vehicle vs. NPY; n = 6). Blood glucose levels were unaffected by intracerebroventricular administration of NPY, but animals receiving either 20 or 50 mu g displayed increased plasma levels of insulin and cortisol at few time points. To assess the pharmacological specificity of this response, a novel Y1 antagonist, [(Ile,Glu,Pro,Daba,Tyr,Arg,Leu,Arg,Tyr-NH2)(2) cyclic (2,4'),(2',4)-diamide] (Y1(ANT)), was synthesized. Receptor binding experiments demonstrated that Y1(ANT) preferentially binds to Y1 and Y4 receptors (pK(i) 10.12 +/- 0.06 and 9.11 +/- 0.05 nmol/L, respectively). Functional analysis revealed that Y1(ANT) is a Y1 antagonist and a partial Y4 agonist. Central administration of Y1(ANT) blocked NPY-induced feeding. In food-deprived monkeys, Y1(ANT) attenuated the feeding response. However, Y1(ANT) had no effect on food intake in satiated monkeys. Thus, endogenous NPY is likely to be involved in the regulation of food intake in the nonhuman primate, and this effect is at least partially mediated via Y1-like receptors.