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PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells
BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR)-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: R...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553172/ https://www.ncbi.nlm.nih.gov/pubmed/23372643 http://dx.doi.org/10.1371/journal.pone.0050128 |
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author | Kim, Hyo-Sup Hwang, You-Cheol Koo, Seung-Hoi Park, Kyong Soo Lee, Myung-Shik Kim, Kwang-Won Lee, Moon-Kyu |
author_facet | Kim, Hyo-Sup Hwang, You-Cheol Koo, Seung-Hoi Park, Kyong Soo Lee, Myung-Shik Kim, Kwang-Won Lee, Moon-Kyu |
author_sort | Kim, Hyo-Sup |
collection | PubMed |
description | BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR)-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ) and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA) receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation. |
format | Online Article Text |
id | pubmed-3553172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35531722013-01-31 PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells Kim, Hyo-Sup Hwang, You-Cheol Koo, Seung-Hoi Park, Kyong Soo Lee, Myung-Shik Kim, Kwang-Won Lee, Moon-Kyu PLoS One Research Article BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR)-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ) and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA) receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation. Public Library of Science 2013-01-23 /pmc/articles/PMC3553172/ /pubmed/23372643 http://dx.doi.org/10.1371/journal.pone.0050128 Text en © 2013 Kim 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 Kim, Hyo-Sup Hwang, You-Cheol Koo, Seung-Hoi Park, Kyong Soo Lee, Myung-Shik Kim, Kwang-Won Lee, Moon-Kyu PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title | PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title_full | PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title_fullStr | PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title_full_unstemmed | PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title_short | PPAR-γ Activation Increases Insulin Secretion through the Up-regulation of the Free Fatty Acid Receptor GPR40 in Pancreatic β-Cells |
title_sort | ppar-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor gpr40 in pancreatic β-cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553172/ https://www.ncbi.nlm.nih.gov/pubmed/23372643 http://dx.doi.org/10.1371/journal.pone.0050128 |
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