Garfield, AS;
Davies, JR;
Burke, LK;
Furby, HV;
Wilkinson, LS;
Heisler, LK;
Isles, AR;
(2016)
Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite.
Molecular Brain
, 9
, Article 95. 10.1186/s13041-016-0277-4.
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Abstract
Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) 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-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR 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-HT2CR pre-mRNA. The 5-HT2CR 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-HT2CR 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-HT2CR agonist, the new obesity treatment lorcaserin.
| Type: | Article |
|---|---|
| Title: | Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13041-016-0277-4 |
| Publisher version: | http://doi.org/10.1186/s13041-016-0277-4 |
| Language: | English |
| Additional information: | © The Author(s). 2016. This 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. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Snord115, Prader-Willi syndrome, Serotonin 2C recptor, Alternate splicing, Feeding, NEURONS REGULATE ENERGY, SMALL NUCLEOLAR RNAS, FOOD-INTAKE, SEROTONIN, MICE, DELETION, OBESITY, 2C, IDENTIFICATION, FENFLURAMINE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10024946 |
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