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Effects of Peptide YY[3–36] on Short-Term Food Intake in Mice Are Not Affected by Prevailing Plasma Ghrelin Levels

Pharmacology Department, Amylin Pharmaceuticals, Inc. (S.H.A., W.B.W., J.R.P.), San Diego, California 92121; and Division of Gastroenterology, Tufts-New England Medical Center (S.E.S., A.B.L.), Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Dr. Sean H. Adams, Pharmacology Department, Amylin Pharmaceuticals, Inc., 9360 Town Centre Drive, San Diego, California 92121. E-mail: sadams{at}amylin.com.

The gut-derived hormones peptide YY[3–36] (PYY[3–36]) and ghrelin are believed to influence similar hypothalamic circuits, albeit with opposing actions on energy balance. Thus, we carried out a series of studies to evaluate the interaction of these hormones on short-term food intake responses in mice. Intraperitoneal PYY[3–36] injection reduced short-term food intake by up to 50% in overnight-fasted mice and in postabsorptive animals during the early and late light cycle. This effect was not sensitive to the prevailing endogenous plasma acyl-ghrelin concentrations, which ranged from high physiological (overnight-fasted, 1252 ± 108 pg/ml) to low levels (late light cycle, 402 ± 33 pg/ml). PYY[3–36] administration did not reduce plasma total or acyl-ghrelin concentration in conjunction with its anorexigenic actions. Ghrelin increased short-term food intake by up to 1.8-fold in mice treated ip in the early light cycle, but was ineffective in animals treated after an overnight fast or during the late light cycle. Ghrelin did not increase food intake or GH secretion unless plasma levels were increased above high physiological fasting values. The anorexigenic effect of PYY[3–36] over a range of doses was not compromised by coinjection of ghrelin, and PYY[3–36] reduced food intake in agouti mice, which lack fully functional melanocortin signaling. These results in mice support a model in which 1) PYY[3–36] diminishes short-term food intake at least in part through mechanisms distinct from the neuropeptide Y/proopiomelanocortin neural circuits engaged by ghrelin; and 2) a reduction in circulating ghrelin is not requisite for the anorexigenic effects of PYY[3–36].

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