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Gut hormone PYY3-36 physiologically inhibits food intake

Abstract

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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Figure 1: Feeding response to PYY3-36 in rats and c-Fos expression in PomcEGFP mice.
Figure 2: Feeding effects of intra-arcuate injection of PYY3-36 in rats and of i.p. PYY3-36 in Y2r-null mice.
Figure 3: Electrophysiological and neuropeptide responses to PYY3-36 and Y2A.
Figure 4: Effect of PYY3-36 infusion on appetite and food intake in humans.

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Acknowledgements

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.

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Correspondence to Stephen R. Bloom.

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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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