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

Celia de la Calle Arregui, Ana Belén Plata-Gómez, Nerea Deleyto-Seldas, Fernando García, Ana Ortega-Molina, Julio Abril-Garrido, Elena Rodriguez, Ivan Nemazanyy, Laura Tribouillard, Alba Martino, Eduardo Caleiras, Ramón Campos-Olivas, Francisca Mulero, Mathieu Laplante, Javier Muñoz, Mario Pende, Guadalupe Sabio, David M. Sabatini and Alejo Efeyan ()
Additional contact information
Celia de la Calle Arregui: Spanish National Cancer Research Centre (CNIO)
Ana Belén Plata-Gómez: Spanish National Cancer Research Centre (CNIO)
Nerea Deleyto-Seldas: Spanish National Cancer Research Centre (CNIO)
Fernando García: Spanish National Cancer Research Centre (CNIO)
Ana Ortega-Molina: Spanish National Cancer Research Centre (CNIO)
Julio Abril-Garrido: Spanish National Cancer Research Centre (CNIO)
Elena Rodriguez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ivan Nemazanyy: Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633
Laura Tribouillard: Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval
Alba Martino: Histopathology Unit. Spanish National Cancer Research Centre (CNIO)
Eduardo Caleiras: Histopathology Unit. Spanish National Cancer Research Centre (CNIO)
Ramón Campos-Olivas: Spanish National Cancer Research Centre (CNIO)
Francisca Mulero: Spanish National Cancer Research Centre (CNIO)
Mathieu Laplante: Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval
Javier Muñoz: Spanish National Cancer Research Centre (CNIO)
Mario Pende: Université de Paris
Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
David M. Sabatini: Nine Cambridge Center
Alejo Efeyan: Spanish National Cancer Research Centre (CNIO)

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23857-8

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