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Translational control of murine adiponectin expression by an upstream open reading frame element
Adiponectin, an adipocyte-specific secretory protein encoded by the ADIPOQ gene has a causal role in insulin resistance. Anti-diabetic drugs increase plasma adiponectin by a poorly understood, post-transcriptional mechanism enhancing insulin sensitivity. Deletion analysis of a reporter bearing the m...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501164/ https://www.ncbi.nlm.nih.gov/pubmed/37702393 http://dx.doi.org/10.1080/15476286.2023.2256094 |
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author | Vasu, Kommireddy Ramachandiran, Iyappan Chechi, Aayushi Khan, Krishnendu Khan, Debjit Kaufman, Randall Fox, Paul L. |
author_facet | Vasu, Kommireddy Ramachandiran, Iyappan Chechi, Aayushi Khan, Krishnendu Khan, Debjit Kaufman, Randall Fox, Paul L. |
author_sort | Vasu, Kommireddy |
collection | PubMed |
description | Adiponectin, an adipocyte-specific secretory protein encoded by the ADIPOQ gene has a causal role in insulin resistance. Anti-diabetic drugs increase plasma adiponectin by a poorly understood, post-transcriptional mechanism enhancing insulin sensitivity. Deletion analysis of a reporter bearing the mouse Adipoq mRNA 5’-leader identified an inhibitory cis-regulatory sequence. The 5’-leader harbours two potential upstream open reading frames (uORFs) overlapping the principal downstream ORF. Mutation of the uORF ATGs increased reporter translation ~3-fold, indicative of a functional uORF. uORFs are common in mammalian mRNAs; however, only a select group resist translational repression by the integrated stress response (ISR). Thapsigargin (TG), which induces endoplasmic reticulum (ER) stress and the ISR, enhanced expression of a reporter bearing the Adipoq 5’-leader; polysome profiling verified translation-stimulation. TG-stimulated translation was absent in cells defective in Ser(51) phosphorylation of eukaryotic initiation factor 2α (eIF2α), required for the ISR. To determine its role in expression and function of endogenous adiponectin, the upstream uORF was disrupted by CRISPR-Cas9-mediated mutagenesis of differentiated mouse 3T3-L1 adipocytes. uORF disruption in adipocytes increased adiponectin expression, triacylglycerol accumulation, and glucose uptake, and inhibited paracrine muscle and liver cell expression of gluconeogenic enzymes, establishing an important role of the uORF in adiponectin-mediated responses to stress. |
format | Online Article Text |
id | pubmed-10501164 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-105011642023-09-15 Translational control of murine adiponectin expression by an upstream open reading frame element Vasu, Kommireddy Ramachandiran, Iyappan Chechi, Aayushi Khan, Krishnendu Khan, Debjit Kaufman, Randall Fox, Paul L. RNA Biol Research Paper Adiponectin, an adipocyte-specific secretory protein encoded by the ADIPOQ gene has a causal role in insulin resistance. Anti-diabetic drugs increase plasma adiponectin by a poorly understood, post-transcriptional mechanism enhancing insulin sensitivity. Deletion analysis of a reporter bearing the mouse Adipoq mRNA 5’-leader identified an inhibitory cis-regulatory sequence. The 5’-leader harbours two potential upstream open reading frames (uORFs) overlapping the principal downstream ORF. Mutation of the uORF ATGs increased reporter translation ~3-fold, indicative of a functional uORF. uORFs are common in mammalian mRNAs; however, only a select group resist translational repression by the integrated stress response (ISR). Thapsigargin (TG), which induces endoplasmic reticulum (ER) stress and the ISR, enhanced expression of a reporter bearing the Adipoq 5’-leader; polysome profiling verified translation-stimulation. TG-stimulated translation was absent in cells defective in Ser(51) phosphorylation of eukaryotic initiation factor 2α (eIF2α), required for the ISR. To determine its role in expression and function of endogenous adiponectin, the upstream uORF was disrupted by CRISPR-Cas9-mediated mutagenesis of differentiated mouse 3T3-L1 adipocytes. uORF disruption in adipocytes increased adiponectin expression, triacylglycerol accumulation, and glucose uptake, and inhibited paracrine muscle and liver cell expression of gluconeogenic enzymes, establishing an important role of the uORF in adiponectin-mediated responses to stress. Taylor & Francis 2023-09-13 /pmc/articles/PMC10501164/ /pubmed/37702393 http://dx.doi.org/10.1080/15476286.2023.2256094 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Research Paper Vasu, Kommireddy Ramachandiran, Iyappan Chechi, Aayushi Khan, Krishnendu Khan, Debjit Kaufman, Randall Fox, Paul L. Translational control of murine adiponectin expression by an upstream open reading frame element |
title | Translational control of murine adiponectin expression by an upstream open reading frame element |
title_full | Translational control of murine adiponectin expression by an upstream open reading frame element |
title_fullStr | Translational control of murine adiponectin expression by an upstream open reading frame element |
title_full_unstemmed | Translational control of murine adiponectin expression by an upstream open reading frame element |
title_short | Translational control of murine adiponectin expression by an upstream open reading frame element |
title_sort | translational control of murine adiponectin expression by an upstream open reading frame element |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501164/ https://www.ncbi.nlm.nih.gov/pubmed/37702393 http://dx.doi.org/10.1080/15476286.2023.2256094 |
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