Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes
REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by in...
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| Veröffentlicht in: | PloS one 2012-12, Vol.7 (12), p.e52154-e52154 |
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| creator | Regazzetti, Claire Dumas, Karine Le Marchand-Brustel, Yannick Peraldi, Pascal Tanti, Jean-François Giorgetti-Peraldi, Sophie |
| description | REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin. |
| doi_str_mv | 10.1371/journal.pone.0052154 |
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Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0052154</identifier><identifier>PMID: 23272222</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3T3-L1 Cells ; Adipocytes ; Adipocytes - drug effects ; Adipocytes - metabolism ; Animals ; Biology ; Cancer ; Cell growth ; Deoxyribonucleic acid ; Development Biology ; Diabetes ; DNA ; DNA damage ; DNA repair ; Enzyme Activation ; Feedback loops ; Growth factors ; HEK293 Cells ; Humans ; Hypoxia ; Inhibition ; Insulin ; Insulin - metabolism ; Insulin - pharmacology ; Insulin resistance ; Kinases ; Life Sciences ; Ligases ; Lipogenesis ; MAP Kinase Signaling System - drug effects ; Medicine ; Mice ; Musculoskeletal system ; Negative feedback ; Obesity ; Phosphorylation ; Proteasome Endopeptidase Complex - metabolism ; Proteasomes ; Proteins ; Proteolysis ; Rapamycin ; Rodents ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; siRNA ; Transcription Factors - metabolism ; Type 2 diabetes ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e52154-e52154</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Regazzetti 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>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2012 Regazzetti et al 2012 Regazzetti et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c627t-17cc081932903a8a2ec55cbfefc9fb53a85126626ec7d03e84a0feb83f5ed343</citedby><cites>FETCH-LOGICAL-c627t-17cc081932903a8a2ec55cbfefc9fb53a85126626ec7d03e84a0feb83f5ed343</cites><orcidid>0000-0003-1782-1318</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525563/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525563/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23272222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00771056$$DView record in HAL$$Hfree_for_read</backlink></links><search><contributor>Alquier, Thierry</contributor><creatorcontrib>Regazzetti, Claire</creatorcontrib><creatorcontrib>Dumas, Karine</creatorcontrib><creatorcontrib>Le Marchand-Brustel, Yannick</creatorcontrib><creatorcontrib>Peraldi, Pascal</creatorcontrib><creatorcontrib>Tanti, Jean-François</creatorcontrib><creatorcontrib>Giorgetti-Peraldi, Sophie</creatorcontrib><title>Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin.</description><subject>3T3-L1 Cells</subject><subject>Adipocytes</subject><subject>Adipocytes - drug effects</subject><subject>Adipocytes - metabolism</subject><subject>Animals</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cell growth</subject><subject>Deoxyribonucleic acid</subject><subject>Development Biology</subject><subject>Diabetes</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Enzyme Activation</subject><subject>Feedback loops</subject><subject>Growth factors</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Inhibition</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin - pharmacology</subject><subject>Insulin resistance</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Ligases</subject><subject>Lipogenesis</subject><subject>MAP Kinase Signaling System - 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drug effects</topic><topic>Adipocytes - metabolism</topic><topic>Animals</topic><topic>Biology</topic><topic>Cancer</topic><topic>Cell growth</topic><topic>Deoxyribonucleic acid</topic><topic>Development Biology</topic><topic>Diabetes</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>Enzyme Activation</topic><topic>Feedback loops</topic><topic>Growth factors</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Inhibition</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin - pharmacology</topic><topic>Insulin resistance</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Ligases</topic><topic>Lipogenesis</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medicine</topic><topic>Mice</topic><topic>Musculoskeletal system</topic><topic>Negative feedback</topic><topic>Obesity</topic><topic>Phosphorylation</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteasomes</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Rapamycin</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signal Transduction - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</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>Regazzetti, Claire</au><au>Dumas, Karine</au><au>Le Marchand-Brustel, Yannick</au><au>Peraldi, Pascal</au><au>Tanti, Jean-François</au><au>Giorgetti-Peraldi, Sophie</au><au>Alquier, Thierry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-18</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e52154</spage><epage>e52154</epage><pages>e52154-e52154</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>REDD1 (Regulated in development and DNA damage response 1) is a hypoxia and stress response gene and is a negative regulator of mTORC1. Since mTORC1 is involved in the negative feedback loop of insulin signaling, we have studied the role of REDD1 on insulin signaling pathway and its regulation by insulin. In human and murine adipocytes, insulin transiently stimulates REDD1 expression through a MEK dependent pathway. In HEK-293 cells, expression of a constitutive active form of MEK stabilizes REDD1 and protects REDD1 from proteasomal degradation mediated by CUL4A-DDB1 ubiquitin ligase complex. In 3T3-L1 adipocytes, silencing of REDD1 with siRNA induces an increase of mTORC1 activity as well as an inhibition of insulin signaling pathway and lipogenesis. Rapamycin, a mTORC1 inhibitor, restores the insulin signaling after downregulation of REDD1 expression. This observation suggests that REDD1 positively regulates insulin signaling through the inhibition of mTORC1 activity. In conclusion, our results demonstrate that insulin increases REDD1 expression, and that REDD1 participates in the biological response to insulin.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23272222</pmid><doi>10.1371/journal.pone.0052154</doi><orcidid>https://orcid.org/0000-0003-1782-1318</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3-L1 Cells Adipocytes Adipocytes - drug effects Adipocytes - metabolism Animals Biology Cancer Cell growth Deoxyribonucleic acid Development Biology Diabetes DNA DNA damage DNA repair Enzyme Activation Feedback loops Growth factors HEK293 Cells Humans Hypoxia Inhibition Insulin Insulin - metabolism Insulin - pharmacology Insulin resistance Kinases Life Sciences Ligases Lipogenesis MAP Kinase Signaling System - drug effects Medicine Mice Musculoskeletal system Negative feedback Obesity Phosphorylation Proteasome Endopeptidase Complex - metabolism Proteasomes Proteins Proteolysis Rapamycin Rodents Signal transduction Signal Transduction - drug effects Signaling siRNA Transcription Factors - metabolism Type 2 diabetes Ubiquitin Ubiquitin-protein ligase |
| title | Regulated in development and DNA damage responses -1 (REDD1) protein contributes to insulin signaling pathway in adipocytes |
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