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PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment

The nuclear receptor PPARγ is essential to maintain whole-body glucose homeostasis and insulin sensitivity, acting as a master regulator of adipogenesis, lipid, and glucose metabolism. Its activation through natural or synthetic ligands induces the recruitment of coactivators, leading to transcripti...

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Autores principales: Dias, Marieli Mariano Gonçalves, Batista, Fernanda Aparecida Heleno, Tittanegro, Thais Helena, de Oliveira, André Gustavo, Le Maire, Albane, Torres, Felipe Rafael, Filho, Helder Veras Ribeiro, Silveira, Leonardo Reis, Figueira, Ana Carolina Migliorini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729135/
https://www.ncbi.nlm.nih.gov/pubmed/33329381
http://dx.doi.org/10.3389/fendo.2020.561256
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author Dias, Marieli Mariano Gonçalves
Batista, Fernanda Aparecida Heleno
Tittanegro, Thais Helena
de Oliveira, André Gustavo
Le Maire, Albane
Torres, Felipe Rafael
Filho, Helder Veras Ribeiro
Silveira, Leonardo Reis
Figueira, Ana Carolina Migliorini
author_facet Dias, Marieli Mariano Gonçalves
Batista, Fernanda Aparecida Heleno
Tittanegro, Thais Helena
de Oliveira, André Gustavo
Le Maire, Albane
Torres, Felipe Rafael
Filho, Helder Veras Ribeiro
Silveira, Leonardo Reis
Figueira, Ana Carolina Migliorini
author_sort Dias, Marieli Mariano Gonçalves
collection PubMed
description The nuclear receptor PPARγ is essential to maintain whole-body glucose homeostasis and insulin sensitivity, acting as a master regulator of adipogenesis, lipid, and glucose metabolism. Its activation through natural or synthetic ligands induces the recruitment of coactivators, leading to transcription of target genes such as cytokines and hormones. More recently, post translational modifications, such as PPARγ phosphorylation at Ser273 by CDK5 in adipose tissue, have been linked to insulin resistance trough the dysregulation of expression of a specific subset of genes. Here, we investigate how this phosphorylation may disturb the interaction between PPARγ and some coregulator proteins as a new mechanism that may leads to insulin resistance. Through cellular and in vitro assays, we show that PPARγ phosphorylation inhibition increased the activation of the receptor, therefore the increased recruitment of PGC1-α and TIF2 coactivators, whilst decreases the interaction with SMRT and NCoR corepressors. Moreover, our results show a shift in the coregulators interaction domains preferences, suggesting additional interaction interfaces formed between the phosphorylated PPARγ and some coregulator proteins. Also, we observed that the CDK5 presence disturb the PPARγ-coregulator’s synergy, decreasing interaction with PGC1-α, TIF2, and NCoR, but increasing coupling of SMRT. Finally, we conclude that the insulin resistance provoked by PPARγ phosphorylation is linked to a differential coregulators recruitment, which may promote dysregulation in gene expression.
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spelling pubmed-77291352020-12-15 PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment Dias, Marieli Mariano Gonçalves Batista, Fernanda Aparecida Heleno Tittanegro, Thais Helena de Oliveira, André Gustavo Le Maire, Albane Torres, Felipe Rafael Filho, Helder Veras Ribeiro Silveira, Leonardo Reis Figueira, Ana Carolina Migliorini Front Endocrinol (Lausanne) Endocrinology The nuclear receptor PPARγ is essential to maintain whole-body glucose homeostasis and insulin sensitivity, acting as a master regulator of adipogenesis, lipid, and glucose metabolism. Its activation through natural or synthetic ligands induces the recruitment of coactivators, leading to transcription of target genes such as cytokines and hormones. More recently, post translational modifications, such as PPARγ phosphorylation at Ser273 by CDK5 in adipose tissue, have been linked to insulin resistance trough the dysregulation of expression of a specific subset of genes. Here, we investigate how this phosphorylation may disturb the interaction between PPARγ and some coregulator proteins as a new mechanism that may leads to insulin resistance. Through cellular and in vitro assays, we show that PPARγ phosphorylation inhibition increased the activation of the receptor, therefore the increased recruitment of PGC1-α and TIF2 coactivators, whilst decreases the interaction with SMRT and NCoR corepressors. Moreover, our results show a shift in the coregulators interaction domains preferences, suggesting additional interaction interfaces formed between the phosphorylated PPARγ and some coregulator proteins. Also, we observed that the CDK5 presence disturb the PPARγ-coregulator’s synergy, decreasing interaction with PGC1-α, TIF2, and NCoR, but increasing coupling of SMRT. Finally, we conclude that the insulin resistance provoked by PPARγ phosphorylation is linked to a differential coregulators recruitment, which may promote dysregulation in gene expression. Frontiers Media S.A. 2020-11-27 /pmc/articles/PMC7729135/ /pubmed/33329381 http://dx.doi.org/10.3389/fendo.2020.561256 Text en Copyright © 2020 Dias, Batista, Tittanegro, de Oliveira, Le Maire, Torres, Filho, Silveira and Figueira http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Dias, Marieli Mariano Gonçalves
Batista, Fernanda Aparecida Heleno
Tittanegro, Thais Helena
de Oliveira, André Gustavo
Le Maire, Albane
Torres, Felipe Rafael
Filho, Helder Veras Ribeiro
Silveira, Leonardo Reis
Figueira, Ana Carolina Migliorini
PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title_full PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title_fullStr PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title_full_unstemmed PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title_short PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment
title_sort pparγ s273 phosphorylation modifies the dynamics of coregulator proteins recruitment
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729135/
https://www.ncbi.nlm.nih.gov/pubmed/33329381
http://dx.doi.org/10.3389/fendo.2020.561256
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