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

Zhaiyi Zhang, Manli Shen, Paul J. Gresch, Masoud Ghamari-Langroudi, Alexander G. Rabchevsky, Ronald B. Emeson, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)878-894
Number of pages17
JournalEMBO Molecular Medicine
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2016

Bibliographical note

Funding Information:
We are very grateful to the NIMH/Vanderbilt Silvio O. Conte Center for support of these studies (P50 MH096972). This work also was supported by National Institutes of Health RO1 GM083187, R21HD080035, and P20RR020171 to S. S and the Foundation for Prader?Willi Research, and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (8 P20 GM103527-06).

Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

  • alternative splicing
  • brain function
  • food uptake
  • obesity
  • pre-mRNA processing

ASJC Scopus subject areas

  • Molecular Medicine

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