PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells
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. Rat insulinoma INS-1 c...
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| Veröffentlicht in: | PloS one 2013, Vol.8 (1), p.e50128 |
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| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0050128 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0050128</identifier><identifier>PMID: 23372643</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Adenoviridae ; AKT protein ; Animals ; Biology ; Biomedical research ; Ca2+/calmodulin-dependent protein kinase II ; Calcium ; Calcium (intracellular) ; Calcium - metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism ; Cell activation ; Cell growth ; Cell Line, Tumor ; Cholesterol ; Cyclic AMP response element-binding protein ; Cyclic AMP Response Element-Binding Protein - genetics ; Cyclic AMP Response Element-Binding Protein - metabolism ; Diabetes ; Endocrinology ; Fatty acids ; Fatty Acids, Nonesterified - metabolism ; FOXO1 protein ; Gene expression ; Gene Expression Regulation - drug effects ; Genetic Vectors ; Glucose ; Glucose transporter ; Glucose Transporter Type 2 - genetics ; Glucose Transporter Type 2 - metabolism ; GLUT2 protein ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Homeostasis ; Insulin ; Insulin - metabolism ; Insulin Receptor Substrate Proteins - genetics ; Insulin Receptor Substrate Proteins - metabolism ; Insulin Secretion ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; Insulinoma ; Interference ; Intracellular ; Intracellular signalling ; Kinases ; Male ; Medicine ; Metabolism ; Metabolites ; Pancreas ; Peroxisome proliferator-activated receptors ; Phosphorylation - drug effects ; PPAR gamma - agonists ; PPAR gamma - genetics ; PPAR gamma - metabolism ; Programmable logic controllers ; Programmable logic devices ; Proteins ; Rats ; Rats, Inbred OLETF ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Ribonucleic acid ; RNA ; RNA, Small Interfering - genetics ; RNA-mediated interference ; Rodents ; Rosiglitazone ; Signal transduction ; Signal Transduction - drug effects ; Thiazolidinediones - pharmacology ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Up-regulation</subject><ispartof>PloS one, 2013, Vol.8 (1), p.e50128</ispartof><rights>2013 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Kim et al 2013 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-17774e5efd108c6332dedea7525a4452ef0ed6680b120178eab85b19318d89a73</citedby><cites>FETCH-LOGICAL-c526t-17774e5efd108c6332dedea7525a4452ef0ed6680b120178eab85b19318d89a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553172/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553172/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,4010,23845,27900,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23372643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sesti, Giorgio</contributor><creatorcontrib>Kim, Hyo-Sup</creatorcontrib><creatorcontrib>Hwang, You-Cheol</creatorcontrib><creatorcontrib>Koo, Seung-Hoi</creatorcontrib><creatorcontrib>Park, Kyong Soo</creatorcontrib><creatorcontrib>Lee, Myung-Shik</creatorcontrib><creatorcontrib>Kim, Kwang-Won</creatorcontrib><creatorcontrib>Lee, Moon-Kyu</creatorcontrib><title>PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.
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.</description><subject>Activation</subject><subject>Adenoviridae</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Biology</subject><subject>Biomedical research</subject><subject>Ca2+/calmodulin-dependent protein kinase II</subject><subject>Calcium</subject><subject>Calcium (intracellular)</subject><subject>Calcium - metabolism</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism</subject><subject>Cell activation</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cholesterol</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cyclic AMP Response Element-Binding Protein - genetics</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Diabetes</subject><subject>Endocrinology</subject><subject>Fatty acids</subject><subject>Fatty Acids, Nonesterified - metabolism</subject><subject>FOXO1 protein</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genetic Vectors</subject><subject>Glucose</subject><subject>Glucose transporter</subject><subject>Glucose Transporter Type 2 - genetics</subject><subject>Glucose Transporter Type 2 - metabolism</subject><subject>GLUT2 protein</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Homeostasis</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin Receptor Substrate Proteins - genetics</subject><subject>Insulin Receptor Substrate Proteins - metabolism</subject><subject>Insulin Secretion</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Insulinoma</subject><subject>Interference</subject><subject>Intracellular</subject><subject>Intracellular signalling</subject><subject>Kinases</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Pancreas</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Phosphorylation - drug effects</subject><subject>PPAR gamma - agonists</subject><subject>PPAR gamma - genetics</subject><subject>PPAR gamma - metabolism</subject><subject>Programmable logic controllers</subject><subject>Programmable logic devices</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Inbred OLETF</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA-mediated interference</subject><subject>Rodents</subject><subject>Rosiglitazone</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Thiazolidinediones - pharmacology</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Up-regulation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1kttq3DAQhk1paQ7tG5TW0GtvdbAOvimE0CaBQJeQXAvZGu16USxXkgN5gLxQ-x55pmp3nZBc9EYjZv7_m2GYoviE0QJTgb9t_BQG7RajH2CBEEOYyDfFIW4oqThB9O2L_0FxFOMmi6jk_H1xQCgVhNf0sHhYLk-uqse_pe5Sf6dT74eyH7oAOkLMvzi5figj5MyultbBT6t1jlBOYxVgNbm9y9td0gbIj07pPiN7UwboYEw-lGfLqxplYjnqHT_1Xfn4p-rAufiheGe1i_BxjsfFzc8f16fn1eWvs4vTk8uqY4SnCgshamBgDUay45QSAwa0YITpumYELALDuUQtJggLCbqVrM1bwNLIRgt6XHzZc0fno5o3GBWmRMimQaLOiou9wni9UWPob3W4V173apfwYaV0yKM7UEhzawgjhllZW8SltQCklW2jW8tqklnf525TewumgyEF7V5BX1eGfq1W_k5RxigWW8DXGRD87wli-s_I9V7VBR9jAPvcASO1PZUnl9qeippPJds-v5zu2fR0G_Qfg9HANw</recordid><startdate>2013</startdate><enddate>2013</enddate><creator>Kim, Hyo-Sup</creator><creator>Hwang, You-Cheol</creator><creator>Koo, Seung-Hoi</creator><creator>Park, Kyong Soo</creator><creator>Lee, Myung-Shik</creator><creator>Kim, Kwang-Won</creator><creator>Lee, Moon-Kyu</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>2013</creationdate><title>PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells</title><author>Kim, Hyo-Sup ; Hwang, You-Cheol ; Koo, Seung-Hoi ; Park, Kyong Soo ; Lee, Myung-Shik ; Kim, Kwang-Won ; Lee, Moon-Kyu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-17774e5efd108c6332dedea7525a4452ef0ed6680b120178eab85b19318d89a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Activation</topic><topic>Adenoviridae</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Biology</topic><topic>Biomedical research</topic><topic>Ca2+/calmodulin-dependent protein kinase II</topic><topic>Calcium</topic><topic>Calcium (intracellular)</topic><topic>Calcium - metabolism</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism</topic><topic>Cell activation</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cholesterol</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Cyclic AMP Response Element-Binding Protein - genetics</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Diabetes</topic><topic>Endocrinology</topic><topic>Fatty acids</topic><topic>Fatty Acids, Nonesterified - metabolism</topic><topic>FOXO1 protein</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Genetic Vectors</topic><topic>Glucose</topic><topic>Glucose transporter</topic><topic>Glucose Transporter Type 2 - genetics</topic><topic>Glucose Transporter Type 2 - metabolism</topic><topic>GLUT2 protein</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Homeostasis</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin Receptor Substrate Proteins - genetics</topic><topic>Insulin Receptor Substrate Proteins - metabolism</topic><topic>Insulin Secretion</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Insulinoma</topic><topic>Interference</topic><topic>Intracellular</topic><topic>Intracellular signalling</topic><topic>Kinases</topic><topic>Male</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Pancreas</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>Phosphorylation - drug effects</topic><topic>PPAR gamma - agonists</topic><topic>PPAR gamma - genetics</topic><topic>PPAR gamma - metabolism</topic><topic>Programmable logic controllers</topic><topic>Programmable logic devices</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Inbred OLETF</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Small Interfering - genetics</topic><topic>RNA-mediated interference</topic><topic>Rodents</topic><topic>Rosiglitazone</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Thiazolidinediones - pharmacology</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - metabolism</topic><topic>Up-regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Hyo-Sup</creatorcontrib><creatorcontrib>Hwang, You-Cheol</creatorcontrib><creatorcontrib>Koo, Seung-Hoi</creatorcontrib><creatorcontrib>Park, Kyong Soo</creatorcontrib><creatorcontrib>Lee, Myung-Shik</creatorcontrib><creatorcontrib>Kim, Kwang-Won</creatorcontrib><creatorcontrib>Lee, Moon-Kyu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection (ProQuest)</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Hyo-Sup</au><au>Hwang, You-Cheol</au><au>Koo, Seung-Hoi</au><au>Park, Kyong Soo</au><au>Lee, Myung-Shik</au><au>Kim, Kwang-Won</au><au>Lee, Moon-Kyu</au><au>Sesti, Giorgio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013</date><risdate>2013</risdate><volume>8</volume><issue>1</issue><spage>e50128</spage><pages>e50128-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23372643</pmid><doi>10.1371/journal.pone.0050128</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013, Vol.8 (1), p.e50128 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1327899074 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Adenoviridae AKT protein Animals Biology Biomedical research Ca2+/calmodulin-dependent protein kinase II Calcium Calcium (intracellular) Calcium - metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism Cell activation Cell growth Cell Line, Tumor Cholesterol Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - genetics Cyclic AMP Response Element-Binding Protein - metabolism Diabetes Endocrinology Fatty acids Fatty Acids, Nonesterified - metabolism FOXO1 protein Gene expression Gene Expression Regulation - drug effects Genetic Vectors Glucose Glucose transporter Glucose Transporter Type 2 - genetics Glucose Transporter Type 2 - metabolism GLUT2 protein Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Homeostasis Insulin Insulin - metabolism Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin Secretion Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - pathology Insulinoma Interference Intracellular Intracellular signalling Kinases Male Medicine Metabolism Metabolites Pancreas Peroxisome proliferator-activated receptors Phosphorylation - drug effects PPAR gamma - agonists PPAR gamma - genetics PPAR gamma - metabolism Programmable logic controllers Programmable logic devices Proteins Rats Rats, Inbred OLETF Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Ribonucleic acid RNA RNA, Small Interfering - genetics RNA-mediated interference Rodents Rosiglitazone Signal transduction Signal Transduction - drug effects Thiazolidinediones - pharmacology Trans-Activators - genetics Trans-Activators - metabolism Up-regulation |
| title | PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells |
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