Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite

Alastair S Garfield, Jennifer R Davies, Luke K Burke, Hannah V Furby, Lawrence S Wilkinson, Lora K Heisler, Anthony R Isles

Research output: Contribution to journalArticle

18 Citations (Scopus)
4 Downloads (Pure)

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.

Original languageEnglish
Article number95
JournalMolecular brain
Volume9
Issue number1
DOIs
Publication statusPublished - 8 Dec 2016

Fingerprint

Prader-Willi Syndrome
Receptor, Serotonin, 5-HT2C
Alternative Splicing
Appetite
Serotonin
AIDS-Related Complex
Hyperphagia
RNA Precursors
Obesity
Small Nucleolar RNA
Melanocortins
Appetite Regulation
Appetite Depressants
Pro-Opiomelanocortin
Arcuate Nucleus of Hypothalamus
RNA
Neurons
Messenger RNA

Keywords

  • Snord115
  • Prader-Willi syndrome
  • Serotonin 2C receptor
  • Alternate splicing
  • feeding

Cite this

Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite. / Garfield, Alastair S; Davies, Jennifer R; Burke, Luke K; Furby, Hannah V; Wilkinson, Lawrence S; Heisler, Lora K; Isles, Anthony R.

In: Molecular brain, Vol. 9, No. 1, 95, 08.12.2016.

Research output: Contribution to journalArticle

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 5HT2C receptor mediated appetite. In: Molecular brain. 2016 ; Vol. 9, No. 1.
@article{d6dd7b0cef274bc2aa74331eddbc6095,
title = "Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite",
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.",
keywords = "Snord115, Prader-Willi syndrome, Serotonin 2C receptor , Alternate splicing, feeding",
author = "Garfield, {Alastair S} and Davies, {Jennifer R} and Burke, {Luke K} and Furby, {Hannah V} and Wilkinson, {Lawrence S} and Heisler, {Lora K} and Isles, {Anthony R}",
note = "Funding This work was supported by grants from the Prader-Willi Syndrome Association UK, Wellcome Trust (WT098012; WT081713 to LKH), the Foundation for Prader-Willi Research (to ARI), the Medical Research Council (G0801418) and the Biotechnology and Biological Research Council (BB/J016756/1; to LSW and ARI).",
year = "2016",
month = "12",
day = "8",
doi = "10.1186/s13041-016-0277-4",
language = "English",
volume = "9",
journal = "Molecular brain",
issn = "1756-6606",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite

AU - Garfield, Alastair S

AU - Davies, Jennifer R

AU - Burke, Luke K

AU - Furby, Hannah V

AU - Wilkinson, Lawrence S

AU - Heisler, Lora K

AU - Isles, Anthony R

N1 - Funding This work was supported by grants from the Prader-Willi Syndrome Association UK, Wellcome Trust (WT098012; WT081713 to LKH), the Foundation for Prader-Willi Research (to ARI), the Medical Research Council (G0801418) and the Biotechnology and Biological Research Council (BB/J016756/1; to LSW and ARI).

PY - 2016/12/8

Y1 - 2016/12/8

N2 - 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.

AB - 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.

KW - Snord115

KW - Prader-Willi syndrome

KW - Serotonin 2C receptor

KW - Alternate splicing

KW - feeding

U2 - 10.1186/s13041-016-0277-4

DO - 10.1186/s13041-016-0277-4

M3 - Article

VL - 9

JO - Molecular brain

JF - Molecular brain

SN - 1756-6606

IS - 1

M1 - 95

ER -