PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice

Authors

  • Yan-Chuan Shi,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
    2. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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  • Zhou Lin,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
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  • Jackie Lau,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
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  • Hui Zhang,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
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  • Miyuki Yagi,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
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  • Isabella Kanzler,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
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  • Amanda Sainsbury,

    1. The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School The University of Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
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  • Herbert Herzog,

    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
    2. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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    • Herbert Herzog and Shu Lin contributed equally to this work.

  • Shu Lin

    Corresponding author
    1. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
    2. Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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    • Herbert Herzog and Shu Lin contributed equally to this work.


  • Funding agencies: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia with grant #427661 and fellowships to SL, AS, and HH.

    Author contributions: Conceived and designed the experiments: SL HH. Carried out the experiments: SL YCS ZL JL IK MY. Analyzed the data: SL YCS. Wrote the manuscript: YCS HH AS SL. All authors had final approval of the submitted and published versions.

  • Disclosure: The authors declared no conflict of interest.

Abstract

Objective

Peptide YY (PYY3-36) and pancreatic polypeptide (PP) potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake.

Design and Methods

Fasted WT, Y2/, Y4/, or Y2Y4/ mice were i.p. administrated with saline, PYY3-36, and/or PP.

Results

Combined injection of PYY3-36 and PP reduces food intake in an additive manner was demonstrated in this study. This effect is mediated via Y2 and Y4 receptors, respectively. It was demonstrated that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the arcuate nucleus (Arc), paraventricular nucleus, and dorso-medial nucleus of the hypothalamus (DMH) are activated with minimal responses seen in the ventro-medial nucleus of the hypothalamus (VMH) and lateral hypothalamic area (LHA) of WT mice. These effects are absent in Y2/ mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH, and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction.

Conclusions

These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.

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