Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus1. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons2 in the arcuate nucleus, which is accessible to peripheral hormones3. Peptide YY3-36 (PYY3-36), a Y2R agonist4, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal5,6,7. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons8. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.
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We thank D. Withers, J. Gardiner, J. Smart, D. Morgan, A. Sainsbury, J. Brundage, J. Williams, K. Takahashi, K. Grove, A. Kennedy, H. Cox and the Hammersmith hypothalamic team for assistance; and G. Williams for providing the antibody to NPY.
The authors declare that they have no competing financial interests.
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Batterham, R., Cowley, M., Small, C. et al. Gut hormone PYY3-36 physiologically inhibits food intake. Nature 418, 650–654 (2002). https://doi.org/10.1038/nature00887
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