FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity
FOXO1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive...
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container_title | The Journal of biological chemistry |
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creator | Armoni, Michal Harel, Chava Karni, Shiri Chen, Hui Bar-Yoseph, Fabiana Ver, Marel R Quon, Michael J Karnieli, Eddy |
description | FOXO1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARgamma2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614-30623). However, the mechanisms regulating PPARgamma gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARgamma gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARgamma1 promoter and partially lost their effects on the PPARgamma2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARgamma2 (but not PPARgamma1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARgamma2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARgamma, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARgamma2 promoter may serve as a therapeutic target for type 2 diabetes. |
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A novel paradigm to increase insulin sensitivity</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Armoni, Michal ; Harel, Chava ; Karni, Shiri ; Chen, Hui ; Bar-Yoseph, Fabiana ; Ver, Marel R ; Quon, Michael J ; Karnieli, Eddy</creator><creatorcontrib>Armoni, Michal ; Harel, Chava ; Karni, Shiri ; Chen, Hui ; Bar-Yoseph, Fabiana ; Ver, Marel R ; Quon, Michael J ; Karnieli, Eddy</creatorcontrib><description>FOXO1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARgamma2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614-30623). However, the mechanisms regulating PPARgamma gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARgamma gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARgamma1 promoter and partially lost their effects on the PPARgamma2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARgamma2 (but not PPARgamma1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARgamma2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARgamma, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARgamma2 promoter may serve as a therapeutic target for type 2 diabetes.</description><identifier>ISSN: 0021-9258</identifier><identifier>PMID: 16670091</identifier><language>eng</language><publisher>United States</publisher><subject>Adipocytes - physiology ; Animals ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Gene Expression Regulation ; Genetic Vectors ; Glucose Transporter Type 4 - genetics ; Humans ; Insulin - physiology ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; PPAR gamma - genetics ; Promoter Regions, Genetic ; Protein Biosynthesis ; Rats ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>The Journal of biological chemistry, 2006-07, Vol.281 (29), p.19881-19891</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16670091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Armoni, Michal</creatorcontrib><creatorcontrib>Harel, Chava</creatorcontrib><creatorcontrib>Karni, Shiri</creatorcontrib><creatorcontrib>Chen, Hui</creatorcontrib><creatorcontrib>Bar-Yoseph, Fabiana</creatorcontrib><creatorcontrib>Ver, Marel R</creatorcontrib><creatorcontrib>Quon, Michael J</creatorcontrib><creatorcontrib>Karnieli, Eddy</creatorcontrib><title>FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>FOXO1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARgamma2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614-30623). However, the mechanisms regulating PPARgamma gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARgamma gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARgamma1 promoter and partially lost their effects on the PPARgamma2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARgamma2 (but not PPARgamma1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARgamma2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARgamma, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARgamma2 promoter may serve as a therapeutic target for type 2 diabetes.</description><subject>Adipocytes - physiology</subject><subject>Animals</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Genetic Vectors</subject><subject>Glucose Transporter Type 4 - genetics</subject><subject>Humans</subject><subject>Insulin - physiology</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>PPAR gamma - genetics</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Biosynthesis</subject><subject>Rats</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1UMtOwzAQzAFES-EXkE_cguLYeR2rigJSpV564BatnW1lFMfB61T0f_hQDC172dnRzK5mr5J5luU8bfKiniW3RB9ZLNnwm2TGy7LKsobPk-_19n3LmcfRIxESG9G7L0POIhu9680ePQTnU9DBHCFgF7Uax1_qANYCZzB07IxzdsDhz2ddQE_MDHEwFvyJQWdGp08B6Ykt2eCO2LMRfKQPlgUXpdojEEZAUx-NhAOZeNOE011yvYee8P7SF8lu_bxbvaab7cvbarlJx0LydM-LLm8ayXWptVAgZKYEL2voslrWXNWgqrzQVaG5RNSdFhKF4IiqaRQvarFIHs9rY4DPCSm01pDGvocB3URtWZeyyCsZhQ8X4aQsdu0lY_v_VvED24d3Gg</recordid><startdate>20060721</startdate><enddate>20060721</enddate><creator>Armoni, Michal</creator><creator>Harel, Chava</creator><creator>Karni, Shiri</creator><creator>Chen, Hui</creator><creator>Bar-Yoseph, Fabiana</creator><creator>Ver, Marel R</creator><creator>Quon, Michael J</creator><creator>Karnieli, Eddy</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20060721</creationdate><title>FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity</title><author>Armoni, Michal ; Harel, Chava ; Karni, Shiri ; Chen, Hui ; Bar-Yoseph, Fabiana ; Ver, Marel R ; Quon, Michael J ; Karnieli, Eddy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p541-f15d29941c6cc3ba340b3168ad08481b8ab725c75c14eecdc34e331eeb99b1583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adipocytes - physiology</topic><topic>Animals</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Genetic Vectors</topic><topic>Glucose Transporter Type 4 - genetics</topic><topic>Humans</topic><topic>Insulin - physiology</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>PPAR gamma - genetics</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Biosynthesis</topic><topic>Rats</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Armoni, Michal</creatorcontrib><creatorcontrib>Harel, Chava</creatorcontrib><creatorcontrib>Karni, Shiri</creatorcontrib><creatorcontrib>Chen, Hui</creatorcontrib><creatorcontrib>Bar-Yoseph, Fabiana</creatorcontrib><creatorcontrib>Ver, Marel R</creatorcontrib><creatorcontrib>Quon, Michael J</creatorcontrib><creatorcontrib>Karnieli, Eddy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Armoni, Michal</au><au>Harel, Chava</au><au>Karni, Shiri</au><au>Chen, Hui</au><au>Bar-Yoseph, Fabiana</au><au>Ver, Marel R</au><au>Quon, Michael J</au><au>Karnieli, Eddy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2006-07-21</date><risdate>2006</risdate><volume>281</volume><issue>29</issue><spage>19881</spage><epage>19891</epage><pages>19881-19891</pages><issn>0021-9258</issn><abstract>FOXO1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARgamma2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614-30623). However, the mechanisms regulating PPARgamma gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARgamma gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARgamma1 promoter and partially lost their effects on the PPARgamma2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARgamma2 (but not PPARgamma1) promoter. Progressive 5'-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARgamma2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARgamma, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARgamma2 promoter may serve as a therapeutic target for type 2 diabetes.</abstract><cop>United States</cop><pmid>16670091</pmid><tpages>11</tpages></addata></record> |
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subjects | Adipocytes - physiology Animals Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Gene Expression Regulation Genetic Vectors Glucose Transporter Type 4 - genetics Humans Insulin - physiology Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism PPAR gamma - genetics Promoter Regions, Genetic Protein Biosynthesis Rats Reverse Transcriptase Polymerase Chain Reaction |
title | FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity |
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