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Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice
To study the effects of an analog of the gut-produced hormone peptide YY (PYY(3-36)), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806261/ https://www.ncbi.nlm.nih.gov/pubmed/31074796 http://dx.doi.org/10.1210/en.2019-00100 |
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author | Jones, Edward S Nunn, Nicolas Chambers, Adam P Østergaard, Søren Wulff, Birgitte S Luckman, Simon M |
author_facet | Jones, Edward S Nunn, Nicolas Chambers, Adam P Østergaard, Søren Wulff, Birgitte S Luckman, Simon M |
author_sort | Jones, Edward S |
collection | PubMed |
description | To study the effects of an analog of the gut-produced hormone peptide YY (PYY(3-36)), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified form of the peptide hormone PYY(3-36) with potent selectivity at Y2 receptor (>5000-fold over Y1, 1250-fold over Y4, and 650-fold over Y5 receptor), was tested in vivo and in vitro in mouse models. NNC0165-1273 has fivefold lower relative affinity for Y2 compared with PYY(3-36), but >250-, 192-, and 400-fold higher selectivity, respectively, for the Y1, Y4, and Y5 receptors. NNC0165-1273 produced a reduction in nighttime feeding at a dose at which PYY(3-36) loses efficacy. The normal behavioral satiety sequence observed suggests that NNC0165-1273 is not nauseating and, instead, reduces food intake by producing early satiety. Additionally, NNC0165-1273 blocked ghrelin-induced cFos expression in NPY/AgRP neurons. In vitro electrophysiological recordings showed that, opposite to ghrelin, NNC0165-1273 hyperpolarized NPY/AgRP neurons and reduced action potential frequency. Administration of NNC0165-1273 via subcutaneous osmotic minipump caused a dose-dependent decrease in body weight and fat mass in an obese mouse model. Finally, NNC0165-1273 attenuated the feeding response when NPY/AgRP neurons were activated using ghrelin or more selectively with designer receptors. NNC0165-1273 is nonnauseating and stimulates a satiety response through, at least in part, a direct action on hypothalamic NPY/AgRP neurons. Modification of PYY(3-36) to produce compounds with increased affinity to Y2 receptors may be useful as antiobesity therapies in humans. |
format | Online Article Text |
id | pubmed-6806261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-68062612019-10-28 Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice Jones, Edward S Nunn, Nicolas Chambers, Adam P Østergaard, Søren Wulff, Birgitte S Luckman, Simon M Endocrinology Research Articles To study the effects of an analog of the gut-produced hormone peptide YY (PYY(3-36)), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified form of the peptide hormone PYY(3-36) with potent selectivity at Y2 receptor (>5000-fold over Y1, 1250-fold over Y4, and 650-fold over Y5 receptor), was tested in vivo and in vitro in mouse models. NNC0165-1273 has fivefold lower relative affinity for Y2 compared with PYY(3-36), but >250-, 192-, and 400-fold higher selectivity, respectively, for the Y1, Y4, and Y5 receptors. NNC0165-1273 produced a reduction in nighttime feeding at a dose at which PYY(3-36) loses efficacy. The normal behavioral satiety sequence observed suggests that NNC0165-1273 is not nauseating and, instead, reduces food intake by producing early satiety. Additionally, NNC0165-1273 blocked ghrelin-induced cFos expression in NPY/AgRP neurons. In vitro electrophysiological recordings showed that, opposite to ghrelin, NNC0165-1273 hyperpolarized NPY/AgRP neurons and reduced action potential frequency. Administration of NNC0165-1273 via subcutaneous osmotic minipump caused a dose-dependent decrease in body weight and fat mass in an obese mouse model. Finally, NNC0165-1273 attenuated the feeding response when NPY/AgRP neurons were activated using ghrelin or more selectively with designer receptors. NNC0165-1273 is nonnauseating and stimulates a satiety response through, at least in part, a direct action on hypothalamic NPY/AgRP neurons. Modification of PYY(3-36) to produce compounds with increased affinity to Y2 receptors may be useful as antiobesity therapies in humans. Endocrine Society 2019-05-10 /pmc/articles/PMC6806261/ /pubmed/31074796 http://dx.doi.org/10.1210/en.2019-00100 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by/4.0/ This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Jones, Edward S Nunn, Nicolas Chambers, Adam P Østergaard, Søren Wulff, Birgitte S Luckman, Simon M Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title | Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title_full | Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title_fullStr | Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title_full_unstemmed | Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title_short | Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice |
title_sort | modified peptide yy molecule attenuates the activity of npy/agrp neurons and reduces food intake in male mice |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806261/ https://www.ncbi.nlm.nih.gov/pubmed/31074796 http://dx.doi.org/10.1210/en.2019-00100 |
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