Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles
The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD...
| Autores: | , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/716908 |
| Acceso en línea: | http://hdl.handle.net/10486/716908 https://dx.doi.org/10.3390/ijms222312960 |
| Access Level: | acceso abierto |
| Palabra clave: | Adipocytes Autophagy Glut4 inflammation insulin receptor insulin resistance Neuregulin 4 Medicina |
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Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesiclesDíaz-Sáez, FranciscoBlanco-Sinfreu, CarlaArchilla-Ortega, AdriàSebastian, DavidRomero, MontserratHernández-Alvarez, Maria IsabelMora, SílviaTestar, XavierRicart, WifredoFernández-Real, José ManuelMoreno-Navarrete, José MaríaAragonés López, JuliánCamps, MartaZorzano, AntonioGumà, AnnaAdipocytesAutophagyGlut4inflammationinsulin receptorinsulin resistanceNeuregulin 4MedicinaThe adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagyGrant 534/C/2016 and 201626-30 funded by FUNDACIÓ LA MARATÓ DE TV3, Catalonia, Spain; Grants SAF2016-75246R, SAF2016-76815 and PID2019-105466RA-100 funded by MCIN/AEI/10.13039/501100011033, Madrid, Spain, by “ERDF A way of making Europe”, by the “European Union”; Grant 2017SGR1015 funded by GENERALITAT DE CATALUNYA, Catalonia, Spain; Grant PIE-14/00045 as well as Programs CIBERDEM and INFLAMES funded by ISCIII, Madrid, Spain;¸Grant CIVP18A3942 funded by FUNDACIÓN RAMÓN ARECES, Madrid, SpainMDPIDepartamento de MedicinaFacultad de Medicina20212021-12-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/716908https://dx.doi.org/10.3390/ijms222312960reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7169082026-06-23T12:46:27Z |
| dc.title.none.fl_str_mv |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| title |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| spellingShingle |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles Díaz-Sáez, Francisco Adipocytes Autophagy Glut4 inflammation insulin receptor insulin resistance Neuregulin 4 Medicina |
| title_short |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| title_full |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| title_fullStr |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| title_full_unstemmed |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| title_sort |
Neuregulin 4 downregulation induces insulin resistance in 3t3-l1 adipocytes through inflammation and autophagic degradation of glut4 vesicles |
| dc.creator.none.fl_str_mv |
Díaz-Sáez, Francisco Blanco-Sinfreu, Carla Archilla-Ortega, Adrià Sebastian, David Romero, Montserrat Hernández-Alvarez, Maria Isabel Mora, Sílvia Testar, Xavier Ricart, Wifredo Fernández-Real, José Manuel Moreno-Navarrete, José María Aragonés López, Julián Camps, Marta Zorzano, Antonio Gumà, Anna |
| author |
Díaz-Sáez, Francisco |
| author_facet |
Díaz-Sáez, Francisco Blanco-Sinfreu, Carla Archilla-Ortega, Adrià Sebastian, David Romero, Montserrat Hernández-Alvarez, Maria Isabel Mora, Sílvia Testar, Xavier Ricart, Wifredo Fernández-Real, José Manuel Moreno-Navarrete, José María Aragonés López, Julián Camps, Marta Zorzano, Antonio Gumà, Anna |
| author_role |
author |
| author2 |
Blanco-Sinfreu, Carla Archilla-Ortega, Adrià Sebastian, David Romero, Montserrat Hernández-Alvarez, Maria Isabel Mora, Sílvia Testar, Xavier Ricart, Wifredo Fernández-Real, José Manuel Moreno-Navarrete, José María Aragonés López, Julián Camps, Marta Zorzano, Antonio Gumà, Anna |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Departamento de Medicina Facultad de Medicina |
| dc.subject.none.fl_str_mv |
Adipocytes Autophagy Glut4 inflammation insulin receptor insulin resistance Neuregulin 4 Medicina |
| topic |
Adipocytes Autophagy Glut4 inflammation insulin receptor insulin resistance Neuregulin 4 Medicina |
| description |
The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-12-01 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10486/716908 https://dx.doi.org/10.3390/ijms222312960 |
| url |
http://hdl.handle.net/10486/716908 https://dx.doi.org/10.3390/ijms222312960 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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MDPI |
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MDPI |
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reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
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Universidad Autónoma de Madrid |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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