2026-04-29T02:37:39Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/137342024-11-29T23:19:04Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2021-06-16 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. 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 MTORC1 REVEALS LIVER MODEL Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.