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The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models

Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knock...

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Autores principales: Wang, Zhiyong, Shah, O. Jameel, Hunter, Tony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409189/
https://www.ncbi.nlm.nih.gov/pubmed/22859932
http://dx.doi.org/10.1371/journal.pone.0036961
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author Wang, Zhiyong
Shah, O. Jameel
Hunter, Tony
author_facet Wang, Zhiyong
Shah, O. Jameel
Hunter, Tony
author_sort Wang, Zhiyong
collection PubMed
description Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes.
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spelling pubmed-34091892012-08-02 The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models Wang, Zhiyong Shah, O. Jameel Hunter, Tony PLoS One Research Article Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. Public Library of Science 2012-07-31 /pmc/articles/PMC3409189/ /pubmed/22859932 http://dx.doi.org/10.1371/journal.pone.0036961 Text en © 2012 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wang, Zhiyong
Shah, O. Jameel
Hunter, Tony
The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title_full The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title_fullStr The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title_full_unstemmed The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title_short The Transcriptional Coactivators p/CIP and SRC-1 Control Insulin Resistance through IRS1 in Obesity Models
title_sort transcriptional coactivators p/cip and src-1 control insulin resistance through irs1 in obesity models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409189/
https://www.ncbi.nlm.nih.gov/pubmed/22859932
http://dx.doi.org/10.1371/journal.pone.0036961
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