at the CNIC

Month: June 2021

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 de Martino, Eduardo Caleiras, Ramón Campos-Olivas, Francisca Mulero, Mathieu Laplante, Javier Muñoz, Mario Pende, Guadalupe Sabio, David M. Sabatini & Alejo Efeyan.

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.

mTORC1 in adaptation to fasting.
mTORC1 in adaptation to fasting.

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.

Premio de Investigación Fundación Dr. Antoni Esteve 2021

El tribunal internacional que cada dos años concede el Premio de Investigación Fundación Dr. Antoni Esteve ha considerado nuestro artículo científico p38γ is essential for cell cycle progression and liver tumorigenesis como la publicación farmacológica más importante publicada por un autor español entre 2019 y 2020.

Premio de Investigación Fundación Dr. Antoni Esteve 2021

Además, han reconocido con una mención honorífica un trabajo del grupo de Rubén Nogueiras y Luisa Seoane, y cuya primera firmante, Cintia Folgueira se encuentra ahora en nuestro grupo de investigación.

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