2026-04-29T02:37:48Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/137342024-11-29T23:19:04Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
de la Calle Arregui, Celia
author
Plata-Gómez, Ana Belén
author
Deleyto-Seldas, Nerea
author
García, Fernando
author
Ortega-Molina, Ana
author
Abril-Garrido, Julio
author
Rodriguez, Elena
author
Nemazanyy, Ivan
author
Tribouillard, Laura
author
de Martino, Alba
author
Caleiras, Eduardo
author
Laplante, Mathieu
author
Muñoz, Javier
author
Pende, Mario
author
Sabio, Guadalupe
author
Sabatini, David M
author
Efeyan, Alejo
author
Mulero, Francisca
author
Campos Olivas, Ramon
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Unión Europea. Comisión Europea
funder
Asociación Española Contra el Cáncer
funder
Canadian Institutes of Health Research
2022-03-08T10:47:54Z
2022-03-08T10:47:54Z
2021-06-16
Nat Commun. 2021;12(1):3660.
http://hdl.handle.net/20.500.12105/13734
34135321
10.1038/s41467-021-23857-8
2041-1723
Nature communications
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 RagA (expression of GTP-locked RagA, or RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagAGTP 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 RagAGTP 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.
eng
MTORC1
REVEALS
LIVER
MODEL
Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.
journal article
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
URL
https://repisalud.isciii.es/bitstreams/17ff6e5a-8306-495c-9ee4-a214a5c3b6b5/download
File
MD5
0ec9a063b169649439c9a5941b5ccae3
6171865
application/pdf
Limitedsurvivalandimpairedhepatic_2022.pdf
URL
https://repisalud.isciii.es/bitstreams/b96aaf10-c183-43be-b191-2d2dcfa885a2/download
File
MD5
b090681ccd2e01a63b402cfaf66b529d
6619817
application/pdf
41467_2021_23857_MOESM1_ESM.pdf
URL
https://repisalud.isciii.es/bitstreams/a4277ad0-fd4b-4a28-9c56-e7eacced7229/download
File
MD5
d887cecc59fccc37b5d96e5a55dae5b9
98523
application/pdf
41467_2021_23857_MOESM2_ESM.pdf
URL
https://repisalud.isciii.es/bitstreams/c7afadfe-12f4-451e-add0-e2db27cdbdd8/download
File
MD5
32abc96107b01e05227b12217173ecfe
3766102
application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
Copia de 41467_2021_23857_MOESM3_ESM.xlsx
URL
https://repisalud.isciii.es/bitstreams/6aea4902-2dc7-4c32-a614-64bd2f404f71/download
File
MD5
8b9726a550ca7614c134f25f3c2e5ad3
3133210
application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
Copia de 41467_2021_23857_MOESM4_ESM.xlsx
URL
https://repisalud.isciii.es/bitstreams/fcf94942-a175-4245-a81a-5696b5aee9b1/download
File
MD5
6da58c45b5d7a166711da434b4db3bc8
2654449
application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
Copia de 41467_2021_23857_MOESM5_ESM.xlsx
URL
https://repisalud.isciii.es/bitstreams/2d65b81f-dd95-449b-83e5-464b5cef7d66/download
File
MD5
7509600a7a6a2a321f32905076812928
86686
application/pdf
41467_2021_23857_MOESM6_ESM.pdf
URL
https://repisalud.isciii.es/bitstreams/b8983dc0-e96f-417e-9017-0109d606e4fc/download
File
MD5
0bfcce377c6a9e36d2eddd99c965c48b
113623
text/plain
Limitedsurvivalandimpairedhepatic_2022.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/42d18901-ef53-4720-ba09-06db15d48431/download
File
MD5
ff53962e3de19eee16dbdad31b6a18bb
51763
text/plain
41467_2021_23857_MOESM1_ESM.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/fef807c1-4192-45e8-9c5a-33135aae520e/download
File
MD5
d54ddb88169db4e4079fd74ed7fb789a
664
text/plain
41467_2021_23857_MOESM2_ESM.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/5192ddca-fe51-4244-9a46-57e4454aa2d2/download
File
MD5
adf2b400e098f2cd3b89187be9a09dad
10650
text/plain
41467_2021_23857_MOESM6_ESM.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/176858b9-79a7-4fa6-97a9-95114b5fd2b3/download
File
MD5
419bf4ec8c4049f034a99b36fe1939df
100000
text/plain
Copia de 41467_2021_23857_MOESM3_ESM.xlsx.txt
URL
https://repisalud.isciii.es/bitstreams/351f9e91-e53d-4792-912a-d2ebb3bf4d55/download
File
MD5
ff23a23155477669a736d06986926e7b
100000
text/plain
Copia de 41467_2021_23857_MOESM4_ESM.xlsx.txt
URL
https://repisalud.isciii.es/bitstreams/76169082-4d9e-48d4-acc0-d891d34d30a8/download
File
MD5
1c2c0a8f1f5a97c5b387d5e627cfc424
100000
text/plain
Copia de 41467_2021_23857_MOESM5_ESM.xlsx.txt