Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake
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...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2016-07-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201506030 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331754819649536 |
|---|---|
| author | Zhaiyi Zhang Manli Shen Paul J Gresch Masoud Ghamari‐Langroudi Alexander G Rabchevsky Ronald B Emeson Stefan Stamm |
| author_facet | Zhaiyi Zhang Manli Shen Paul J Gresch Masoud Ghamari‐Langroudi Alexander G Rabchevsky Ronald B Emeson Stefan Stamm |
| author_sort | Zhaiyi Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a6f72dfd59c54ff8a4ad50a869f07a9b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a6f72dfd59c54ff8a4ad50a869f07a9b2025-08-20T03:46:24ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-07-018887889410.15252/emmm.201506030Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intakeZhaiyi Zhang0Manli Shen1Paul J Gresch2Masoud Ghamari‐Langroudi3Alexander G Rabchevsky4Ronald B Emeson5Stefan Stamm6Department of Molecular and Cellular Biochemistry, University of KentuckyDepartment of Molecular and Cellular Biochemistry, University of KentuckyDepartment of Pharmacology, Vanderbilt UniversityDepartment of Molecular Physiology & Biophysics, Vanderbilt UniversitySpinal Cord & Brain Injury, Research Center, University of KentuckyDepartment of Molecular Physiology & Biophysics, Vanderbilt UniversityDepartment of Molecular and Cellular Biochemistry, University of KentuckyAbstract 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.https://doi.org/10.15252/emmm.201506030alternative splicingbrain functionfood uptakeobesitypre‐mRNA processing |
| spellingShingle | Zhaiyi Zhang Manli Shen Paul J Gresch Masoud Ghamari‐Langroudi Alexander G Rabchevsky Ronald B Emeson Stefan Stamm Oligonucleotide‐induced alternative splicing of serotonin 2C receptor reduces food intake EMBO Molecular Medicine alternative splicing brain function food uptake obesity pre‐mRNA processing |
| 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 | alternative splicing brain function food uptake obesity pre‐mRNA processing |
| url | https://doi.org/10.15252/emmm.201506030 |
| work_keys_str_mv | AT zhaiyizhang oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT manlishen oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT pauljgresch oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT masoudghamarilangroudi oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT alexandergrabchevsky oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT ronaldbemeson oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake AT stefanstamm oligonucleotideinducedalternativesplicingofserotonin2creceptorreducesfoodintake |