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This version published online on March 11, 2004
Endocrinology, doi:10.1210/en.2003-1754
A more recent version of this article appeared on June 1, 2004
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Submitted on December 26, 2003
Accepted on March 1, 2004

PYY3-36 Inhibits Food Intake Through a Melanocortin-4 Receptor-Independent Mechanism

Ilia G. Halatchev, Kate L.J. Ellacott, Wei Fan, and Roger D. Cone*

Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098

* To whom correspondence should be addressed. E-mail: cone{at}ohsu.edu.

PYY3-36, a peptide released post-prandially 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 of 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 (CCK), PYY3-36 dose-dependently inhibits food intake by approximately 20-45% over a 3-4 h period post-intraperitoneal (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 both WT and MC4-R- mice, and thus does not appear to be dependent on melanocortin-4 receptor (MC4-R) signaling. Expression of c-Fos, an indirect marker of neuronal activation, was also examined in forebrain and brain stem neurons following IP treatment with a dose of PYY3-36 shown to induce satiety. The peptide induced no significant neuronal activation in the brain stem by this assay, and only modest activation of hypothalamic POMC neurons. Thus, unlike CCK, PYY3-36 induced satiety is atypical, since it does not produce detectable activation of brain stem satiety centers, and is not dependent on MC4-R signaling.




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