Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling
<jats:title>Abstract</jats:title><jats:p>The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
|
| Online Access: | https://hdl.handle.net/1721.1/135647 |
| _version_ | 1811073941689597952 |
|---|---|
| author | de la Calle Arregui, Celia Plata-Gómez, Ana Belén Deleyto-Seldas, Nerea García, Fernando Ortega-Molina, Ana Abril-Garrido, Julio Rodriguez, Elena Nemazanyy, Ivan Tribouillard, Laura de Martino, Alba Caleiras, Eduardo Campos-Olivas, Ramón Mulero, Francisca Laplante, Mathieu Muñoz, Javier Pende, Mario Sabio, Guadalupe Sabatini, David M Efeyan, Alejo |
| author_facet | de la Calle Arregui, Celia Plata-Gómez, Ana Belén Deleyto-Seldas, Nerea García, Fernando Ortega-Molina, Ana Abril-Garrido, Julio Rodriguez, Elena Nemazanyy, Ivan Tribouillard, Laura de Martino, Alba Caleiras, Eduardo Campos-Olivas, Ramón Mulero, Francisca Laplante, Mathieu Muñoz, Javier Pende, Mario Sabio, Guadalupe Sabatini, David M Efeyan, Alejo |
| author_sort | de la Calle Arregui, Celia |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of <jats:italic>RagA</jats:italic> (expression of GTP-locked RagA, or RagA<jats:sup>GTP</jats:sup>) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in <jats:italic>RagA</jats:italic><jats:sup>GTP</jats:sup> mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from <jats:italic>RagA</jats:italic><jats:sup>GTP</jats:sup> mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.</jats:p> |
| first_indexed | 2024-09-23T09:40:35Z |
| format | Article |
| id | mit-1721.1/135647 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:40:35Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1356472021-10-28T04:42:02Z Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling de la Calle Arregui, Celia Plata-Gómez, Ana Belén Deleyto-Seldas, Nerea García, Fernando Ortega-Molina, Ana Abril-Garrido, Julio Rodriguez, Elena Nemazanyy, Ivan Tribouillard, Laura de Martino, Alba Caleiras, Eduardo Campos-Olivas, Ramón Mulero, Francisca Laplante, Mathieu Muñoz, Javier Pende, Mario Sabio, Guadalupe Sabatini, David M Efeyan, Alejo <jats:title>Abstract</jats:title><jats:p>The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of <jats:italic>RagA</jats:italic> (expression of GTP-locked RagA, or RagA<jats:sup>GTP</jats:sup>) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in <jats:italic>RagA</jats:italic><jats:sup>GTP</jats:sup> mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from <jats:italic>RagA</jats:italic><jats:sup>GTP</jats:sup> mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.</jats:p> 2021-10-27T20:24:25Z 2021-10-27T20:24:25Z 2021 2021-07-23T17:46:45Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135647 en 10.1038/s41467-021-23857-8 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | de la Calle Arregui, Celia Plata-Gómez, Ana Belén Deleyto-Seldas, Nerea García, Fernando Ortega-Molina, Ana Abril-Garrido, Julio Rodriguez, Elena Nemazanyy, Ivan Tribouillard, Laura de Martino, Alba Caleiras, Eduardo Campos-Olivas, Ramón Mulero, Francisca Laplante, Mathieu Muñoz, Javier Pende, Mario Sabio, Guadalupe Sabatini, David M Efeyan, Alejo Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title | Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title_full | Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title_fullStr | Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title_full_unstemmed | Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title_short | Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling |
| title_sort | limited survival and impaired hepatic fasting metabolism in mice with constitutive rag gtpase signaling |
| url | https://hdl.handle.net/1721.1/135647 |
| work_keys_str_mv | AT delacallearreguicelia limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT platagomezanabelen limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT deleytoseldasnerea limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT garciafernando limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT ortegamolinaana limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT abrilgarridojulio limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT rodriguezelena limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT nemazanyyivan limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT tribouillardlaura limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT demartinoalba limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT caleiraseduardo limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT camposolivasramon limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT mulerofrancisca limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT laplantemathieu limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT munozjavier limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT pendemario limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT sabioguadalupe limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT sabatinidavidm limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling AT efeyanalejo limitedsurvivalandimpairedhepaticfastingmetabolisminmicewithconstitutiveraggtpasesignaling |