Gut hormone PYY3-36 physiologically inhibits food intake

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus 1 . The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons 2 in the arcuate nucleus, which is accessible to peripheral hormones 3 . Peptide YY 3-36 (PYY 3-36 ), a Y2R agonist 4 , is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal 5 , 6 , 7 . Here we show that peripheral injection of PYY 3-36 in rats inhibits food intake and reduces weight gain. PYY 3-36 also inhibits food intake in mice but not in Y2r -null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY 3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY 3-36 inhibits food intake. PYY 3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons 8 . In humans, infusion of normal postprandial concentrations of PYY 3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY 3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.