Structure-function analysis of stimulation of food intake by neuropeptide Y: Effects of receptor agonists

Abstract

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 necleus (PVN). NPY 1–36 and various COOH-terminal fragments of NPY, two agonist analogues [Leu 31, Pro 34]NPY and NPY 1-4-Aca (ϵ-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 NPY 1–36 induced a dose-dependent increment in food intake. Surprisingly, deletion of NH 2-terminal tyrosine residue did not adversely affect feeding behavior. In fact, NPY 2–36 was consistently more effective than NPY 1–36; the enhancement in feeding by NPY 2–36 was dose-related and was higher than evoked by NPY 1–36 at each dose tested. Further serial deletion of aminoacids at NH 2-terminal resulted in complete loss of activity. In addition, NPY agonist analogue, NPY 1-4-Aca-25-36, failed to stimulate feeding. However, NPY Y 1 receptor agonist, [Leu 31, Pro 34]NPY, but not Y 2 receptor agonist, NPY 13–36, stimulated feeding. These studies show that deletion of NH 2-terminal tyrosine residue renders NPY 2–36 more effective than natural NPY 1–36, and stimulation of feeding by NPY 1–36 and NPY 2–36 is mediated by NPY Y 1 receptor subtypes. Since NPY 1-4-Aca-25-36 and NPY 13–36 were inactive, it suggests 5–12 amino acid residues in NPY 1–36 and NPY 2–36 may be actively engaged in evoking ingestive behavior.