Cargando…

Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction w...

Descripción completa

Detalles Bibliográficos
Autores principales: Foryst-Ludwig, Anna, Clemenz, Markus, Hohmann, Stephan, Hartge, Martin, Sprang, Christiane, Frost, Nikolaj, Krikov, Maxim, Bhanot, Sanjay, Barros, Rodrigo, Morani, Andrea, Gustafsson, Jan-Åke, Unger, Thomas, Kintscher, Ulrich
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2432036/
https://www.ncbi.nlm.nih.gov/pubmed/18584035
http://dx.doi.org/10.1371/journal.pgen.1000108
_version_ 1782156446221205504
author Foryst-Ludwig, Anna
Clemenz, Markus
Hohmann, Stephan
Hartge, Martin
Sprang, Christiane
Frost, Nikolaj
Krikov, Maxim
Bhanot, Sanjay
Barros, Rodrigo
Morani, Andrea
Gustafsson, Jan-Åke
Unger, Thomas
Kintscher, Ulrich
author_facet Foryst-Ludwig, Anna
Clemenz, Markus
Hohmann, Stephan
Hartge, Martin
Sprang, Christiane
Frost, Nikolaj
Krikov, Maxim
Bhanot, Sanjay
Barros, Rodrigo
Morani, Andrea
Gustafsson, Jan-Åke
Unger, Thomas
Kintscher, Ulrich
author_sort Foryst-Ludwig, Anna
collection PubMed
description Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARγ, in vitro and in high-fat diet (HFD)-fed ERβ -/- mice (βERKO) mice. Our in vitro experiments showed that ERβ inhibits ligand-mediated PPARγ-transcriptional activity. That resulted in a blockade of PPARγ-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERβ-mediated inhibition of PPARγ activity. Consistent with the in vitro data, we observed increased PPARγ activity in gonadal fat from HFD-fed βERKO mice. In consonance with enhanced PPARγ activation, HFD-fed βERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPARγ in HFD-fed βERKO mice, PPARγ signaling was disrupted by PPARγ antisense oligonucleotide (ASO). Blockade of adipose PPARγ by ASO reversed the phenotype of βERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPARγ-regulated adiponectin promoter was enhanced in gonadal fat from βERKO mice indicating that the absence of ERβ in adipose tissue results in exaggerated coactivator binding to a PPARγ target promoter. Collectively, our data provide the first evidence that ERβ-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPARγ signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERβ may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ERβ-selective agonists.
format Text
id pubmed-2432036
institution National Center for Biotechnology Information
language English
publishDate 2008
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-24320362008-06-27 Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ Foryst-Ludwig, Anna Clemenz, Markus Hohmann, Stephan Hartge, Martin Sprang, Christiane Frost, Nikolaj Krikov, Maxim Bhanot, Sanjay Barros, Rodrigo Morani, Andrea Gustafsson, Jan-Åke Unger, Thomas Kintscher, Ulrich PLoS Genet Research Article Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARγ, in vitro and in high-fat diet (HFD)-fed ERβ -/- mice (βERKO) mice. Our in vitro experiments showed that ERβ inhibits ligand-mediated PPARγ-transcriptional activity. That resulted in a blockade of PPARγ-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERβ-mediated inhibition of PPARγ activity. Consistent with the in vitro data, we observed increased PPARγ activity in gonadal fat from HFD-fed βERKO mice. In consonance with enhanced PPARγ activation, HFD-fed βERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPARγ in HFD-fed βERKO mice, PPARγ signaling was disrupted by PPARγ antisense oligonucleotide (ASO). Blockade of adipose PPARγ by ASO reversed the phenotype of βERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPARγ-regulated adiponectin promoter was enhanced in gonadal fat from βERKO mice indicating that the absence of ERβ in adipose tissue results in exaggerated coactivator binding to a PPARγ target promoter. Collectively, our data provide the first evidence that ERβ-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPARγ signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERβ may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ERβ-selective agonists. Public Library of Science 2008-06-27 /pmc/articles/PMC2432036/ /pubmed/18584035 http://dx.doi.org/10.1371/journal.pgen.1000108 Text en Foryst-Ludwig 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
Foryst-Ludwig, Anna
Clemenz, Markus
Hohmann, Stephan
Hartge, Martin
Sprang, Christiane
Frost, Nikolaj
Krikov, Maxim
Bhanot, Sanjay
Barros, Rodrigo
Morani, Andrea
Gustafsson, Jan-Åke
Unger, Thomas
Kintscher, Ulrich
Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title_full Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title_fullStr Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title_full_unstemmed Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title_short Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ
title_sort metabolic actions of estrogen receptor beta (erβ) are mediated by a negative cross-talk with pparγ
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2432036/
https://www.ncbi.nlm.nih.gov/pubmed/18584035
http://dx.doi.org/10.1371/journal.pgen.1000108
work_keys_str_mv AT forystludwiganna metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT clemenzmarkus metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT hohmannstephan metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT hartgemartin metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT sprangchristiane metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT frostnikolaj metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT krikovmaxim metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT bhanotsanjay metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT barrosrodrigo metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT moraniandrea metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT gustafssonjanake metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT ungerthomas metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg
AT kintscherulrich metabolicactionsofestrogenreceptorbetaerbaremediatedbyanegativecrosstalkwithpparg