Cargando…

Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake

The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre‐mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full‐len...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Zhaiyi, Shen, Manli, Gresch, Paul J, Ghamari‐Langroudi, Masoud, Rabchevsky, Alexander G, Emeson, Ronald B, Stamm, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967942/
https://www.ncbi.nlm.nih.gov/pubmed/27406820
http://dx.doi.org/10.15252/emmm.201506030
_version_ 1782445595035697152
author Zhang, Zhaiyi
Shen, Manli
Gresch, Paul J
Ghamari‐Langroudi, Masoud
Rabchevsky, Alexander G
Emeson, Ronald B
Stamm, Stefan
author_facet Zhang, Zhaiyi
Shen, Manli
Gresch, Paul J
Ghamari‐Langroudi, Masoud
Rabchevsky, Alexander G
Emeson, Ronald B
Stamm, Stefan
author_sort Zhang, Zhaiyi
collection PubMed
description The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre‐mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full‐length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full‐length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full‐length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro‐opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild‐type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood–brain barrier and its systemic delivery reduced food intake in wild‐type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre‐mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader–Willi syndrome.
format Online
Article
Text
id pubmed-4967942
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-49679422016-08-09 Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake Zhang, Zhaiyi Shen, Manli Gresch, Paul J Ghamari‐Langroudi, Masoud Rabchevsky, Alexander G Emeson, Ronald B Stamm, Stefan EMBO Mol Med Research Articles The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre‐mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full‐length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full‐length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full‐length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro‐opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild‐type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood–brain barrier and its systemic delivery reduced food intake in wild‐type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre‐mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader–Willi syndrome. John Wiley and Sons Inc. 2016-07-12 2016-08 /pmc/articles/PMC4967942/ /pubmed/27406820 http://dx.doi.org/10.15252/emmm.201506030 Text en © 2016 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhang, Zhaiyi
Shen, Manli
Gresch, Paul J
Ghamari‐Langroudi, Masoud
Rabchevsky, Alexander G
Emeson, Ronald B
Stamm, Stefan
Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title_full Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title_fullStr Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title_full_unstemmed Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title_short Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
title_sort oligonucleotide‐induced alternative splicing of serotonin 2c receptor reduces food intake
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967942/
https://www.ncbi.nlm.nih.gov/pubmed/27406820
http://dx.doi.org/10.15252/emmm.201506030
work_keys_str_mv AT zhangzhaiyi oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT shenmanli oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT greschpaulj oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT ghamarilangroudimasoud oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT rabchevskyalexanderg oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT emesonronaldb oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake
AT stammstefan oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake