Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1.
mTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obes...
| Autores: | , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/26221 |
| Acceso en línea: | https://hdl.handle.net/20.500.12105/26221 |
| Access Level: | acceso abierto |
| Palabra clave: | ATGL FoxO1 Rictor Sirt6 UCP1 acetylation adipocyte brown adipose tissue brown fat lipid mTOR mTORC2 metabolism signaling |
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Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1.Jung, Su MyungHung, Chien-MinHildebrand, Samuel RSanchez-Gurmaches, JoanMartinez-Pastor, BarbaraGengatharan, Jivani MWallace, MartinaMukhopadhyay, DimpiMartinez Calejman, CamilaLuciano, Amelia KHsiao, Wen-YuTang, YuefengLi, HuaweiDaniels, Danette LMostoslavsky, RaulMetallo, Christian MGuertin, David AATGLFoxO1RictorSirt6UCP1acetylationadipocytebrown adipose tissuebrown fatlipidmTORmTORC2metabolismsignalingmTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT, and in a pathway distinct from its positive role in anabolic lipid synthesis. This facilitates FoxO1 nuclear retention, enhances lipid uptake and lipolysis, and potentiates UCP1 expression. We provide evidence that SIRT6 is the FoxO1 deacetylase suppressed by mTORC2 and show an endogenous interaction between SIRT6 and mTORC2 in both mouse and human cells. Our findings suggest a new paradigm of mTORC2 function filling an important gap in our understanding of this more mysterious mTOR complex.Cell Press20252025-01-3120192019-08-2220192019-08-22research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.12105/26221reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/262212026-06-12T12:43:37Z |
| dc.title.none.fl_str_mv |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| title |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| spellingShingle |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. Jung, Su Myung ATGL FoxO1 Rictor Sirt6 UCP1 acetylation adipocyte brown adipose tissue brown fat lipid mTOR mTORC2 metabolism signaling |
| title_short |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| title_full |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| title_fullStr |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| title_full_unstemmed |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| title_sort |
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. |
| dc.creator.none.fl_str_mv |
Jung, Su Myung Hung, Chien-Min Hildebrand, Samuel R Sanchez-Gurmaches, Joan Martinez-Pastor, Barbara Gengatharan, Jivani M Wallace, Martina Mukhopadhyay, Dimpi Martinez Calejman, Camila Luciano, Amelia K Hsiao, Wen-Yu Tang, Yuefeng Li, Huawei Daniels, Danette L Mostoslavsky, Raul Metallo, Christian M Guertin, David A |
| author |
Jung, Su Myung |
| author_facet |
Jung, Su Myung Hung, Chien-Min Hildebrand, Samuel R Sanchez-Gurmaches, Joan Martinez-Pastor, Barbara Gengatharan, Jivani M Wallace, Martina Mukhopadhyay, Dimpi Martinez Calejman, Camila Luciano, Amelia K Hsiao, Wen-Yu Tang, Yuefeng Li, Huawei Daniels, Danette L Mostoslavsky, Raul Metallo, Christian M Guertin, David A |
| author_role |
author |
| author2 |
Hung, Chien-Min Hildebrand, Samuel R Sanchez-Gurmaches, Joan Martinez-Pastor, Barbara Gengatharan, Jivani M Wallace, Martina Mukhopadhyay, Dimpi Martinez Calejman, Camila Luciano, Amelia K Hsiao, Wen-Yu Tang, Yuefeng Li, Huawei Daniels, Danette L Mostoslavsky, Raul Metallo, Christian M Guertin, David A |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
|
| dc.subject.none.fl_str_mv |
ATGL FoxO1 Rictor Sirt6 UCP1 acetylation adipocyte brown adipose tissue brown fat lipid mTOR mTORC2 metabolism signaling |
| topic |
ATGL FoxO1 Rictor Sirt6 UCP1 acetylation adipocyte brown adipose tissue brown fat lipid mTOR mTORC2 metabolism signaling |
| description |
mTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT, and in a pathway distinct from its positive role in anabolic lipid synthesis. This facilitates FoxO1 nuclear retention, enhances lipid uptake and lipolysis, and potentiates UCP1 expression. We provide evidence that SIRT6 is the FoxO1 deacetylase suppressed by mTORC2 and show an endogenous interaction between SIRT6 and mTORC2 in both mouse and human cells. Our findings suggest a new paradigm of mTORC2 function filling an important gap in our understanding of this more mysterious mTOR complex. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2019-08-22 2019 2019-08-22 2025 2025-01-31 |
| 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 |
https://hdl.handle.net/20.500.12105/26221 |
| url |
https://hdl.handle.net/20.500.12105/26221 |
| 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-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Cell Press |
| publisher.none.fl_str_mv |
Cell Press |
| dc.source.none.fl_str_mv |
reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII) |
| instname_str |
Instituto de Salud Carlos III (ISCIII) |
| reponame_str |
Repisalud |
| collection |
Repisalud |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869418041972883456 |
| score |
15,811543 |