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

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-23857-8

2041-1723

Celia de la Calle Arregui, Ana Belén Plata-Gómez, Nerea Deleyto-Seldas, Fernando Garcı́a, Ana Ortega-Molina, Julio Abril-Garrido, Elena M. Rodríguez Rodríguez, 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,

PI3K/AKT/mTOR signaling in cancer

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.