Peptide YY3-36 (PYY3-36), a pepticle released postprandially by the gut, has been demonstrated to inhibit food intake. Little is known about the mechanism by which PYY3-36 inhibits food intake, although the peptide has been shown to increase hypothalamic proopiomelanocortin (POMC) mRNA in vivo and to activate POMC neurons in an electrophysiological slice preparation. Understanding the physiology of PYY3-36 is further complicated by the fact that some laboratories have had difficulty demonstrating inhibition of feeding by the peptide in rodents. We demonstrate here that, like cholecystokinin, PYY3-36 dose-dependently inhibits food intake by approximately 20-45% over a 3- to 4-h period post ip administration, with no effect on 12-h food intake. This short-lived satiety effect is not seen in animals that are not thoroughly acclimated to handling and ip injection, thus potentially explaining the difficulty in reproducing the effect. Surprisingly, PYY3-36 was equally efficacious in inducing satiety in wildtype and melanocortin-4 receptor (MC4-R)-deficient mice and thus does not appear to be dependent on MC4-R signaling. The expression of c-Fos, an indirect marker of neuronal activation, was also examined in forsbrain and brainstem neurons after ip treatment with a dose of PYY3-36 shown to induce satiety. The peptide induced no significant neuronal activation in the brainstem by this assay, and only modest activation of hypothalamic POMC neurons. Thus, unlike cholecystokinin, PYY3-36-induced satiety is atypical, because it does not produce detectable activation of brainstem satiety centers and is not dependent on MC4-R signaling.