STRUCTURE-FUNCTION ANALYSIS OF STIMULATION OF FOOD-INTAKE BY NEUROPEPTIDE-Y - EFFECTS OF RECEPTOR AGONISTS

Neuropeptide Y (NPY) is a potent natural orexigenic signal in the rat. In this study, we have compared the effects of several COOH-terminal fragments of NPY and NPY receptor agonists on cumulative food intake in male rats. Rats were implanted with permanent cannulae either into the third cerebroventricle or paraventricular nucleus (PVN). NPY1-36 and various COOH-terminal fragments of NPY, two agonist analogues [Leu31, Pro34]NPY and NPY 1-4-Aca (epsilon-amino-caproic acid)-25-36, were administered intracerebroventricularly (ICV) or directly into the PVN, and the cumulative 2-h food intake response was compared. We observed that peptides that were effective by ICV were also effective when administered into the PVN, but smaller amounts of the peptides were required after PVN injection to evoke an equivalent food intake response. Injection of NPY1-36 induced a dose-dependent increment in food intake. Surprisingly, deletion of NH2-terminal tyrosine residue did not adversely affect feeding behavior. In fact, NPY2-36 was consistently more effective than NPY1-36; the enhancement in feeding by NPY2-36 was dose-related and was higher than evoked by NPY1-36 at each dose tested. Further serial deletion of aminoacids at NH2-terminal resulted in complete loss of activity. In addition, NPY agonist analogue, NPY 1-4-Aca-25-36, failed to stimulate feeding. However, NPY Y1 receptor agonist, [Leu31 Pro34]NPY, but not Y2 receptor agonist, NPY13-36, stimulated feeding. These studies show that deletion of NH2-terminal tyrosine residue renders NPY2-36 more effective than natural NPY1-36, and stimulation of feeding by NPY2-36 is mediated by NPY Y1 receptor subtypes. Since NPY 1-4-Aca-25-36 and NPY13-36 were inactive, it suggests 5-12 amino acid residues in NPY1-36 and NPY2-36 may be actively engaged in evoking ingestive behavior.