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Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite

Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT(2C)R) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesi...

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Autores principales: Garfield, Alastair S., Davies, Jennifer R., Burke, Luke K., Furby, Hannah V., Wilkinson, Lawrence S., Heisler, Lora K., Isles, Anthony R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144496/
https://www.ncbi.nlm.nih.gov/pubmed/27931246
http://dx.doi.org/10.1186/s13041-016-0277-4
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author Garfield, Alastair S.
Davies, Jennifer R.
Burke, Luke K.
Furby, Hannah V.
Wilkinson, Lawrence S.
Heisler, Lora K.
Isles, Anthony R.
author_facet Garfield, Alastair S.
Davies, Jennifer R.
Burke, Luke K.
Furby, Hannah V.
Wilkinson, Lawrence S.
Heisler, Lora K.
Isles, Anthony R.
author_sort Garfield, Alastair S.
collection PubMed
description Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT(2C)R) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT(2C)R in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT(2C)R regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT(2C)R pre-mRNA. The 5-HT(2C)R promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT(2C)R agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT(2C)R agonist, the new obesity treatment lorcaserin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-51444962016-12-15 Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite Garfield, Alastair S. Davies, Jennifer R. Burke, Luke K. Furby, Hannah V. Wilkinson, Lawrence S. Heisler, Lora K. Isles, Anthony R. Mol Brain Research Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT(2C)R) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT(2C)R in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT(2C)R regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT(2C)R pre-mRNA. The 5-HT(2C)R promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT(2C)R agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT(2C)R agonist, the new obesity treatment lorcaserin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users. BioMed Central 2016-12-08 /pmc/articles/PMC5144496/ /pubmed/27931246 http://dx.doi.org/10.1186/s13041-016-0277-4 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Garfield, Alastair S.
Davies, Jennifer R.
Burke, Luke K.
Furby, Hannah V.
Wilkinson, Lawrence S.
Heisler, Lora K.
Isles, Anthony R.
Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title_full Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title_fullStr Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title_full_unstemmed Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title_short Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite
title_sort increased alternate splicing of htr2c in a mouse model for prader-willi syndrome leads disruption of 5ht(2c) receptor mediated appetite
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144496/
https://www.ncbi.nlm.nih.gov/pubmed/27931246
http://dx.doi.org/10.1186/s13041-016-0277-4
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