Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.

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 re...

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Bibliographic Details
Authors: 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, Laplante, Mathieu, Muñoz, Javier, Pende, Mario, Sabio, Guadalupe, Sabatini, David M, Efeyan, Alejo, Mulero, Francisca, Campos Olivas, Ramon
Format: article
Publication Date:2021
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/13734
Online Access:http://hdl.handle.net/20.500.12105/13734
Access Level:Open access
Keyword:Signal Transduction
Animals
Disease Models, Animal
Fasting
Glucose
Homeostasis
Humans
Liver
Mechanistic Target of Rapamycin Complex 1
Mice
Monomeric GTP-Binding Proteins
Nutrients
PPAR alpha
Phenotype
Proteomics
Sirolimus
Transcription, Genetic
Tuberous Sclerosis Complex 1 Protein
Description
Summary: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.

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