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Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling
Name
s41467-021-23857-8.pdf
Description
Published version
Size
5.89 MB
Format
Adobe PDF
Checksum (MD5)
0ec9a063b169649439c9a5941b5ccae3
Author(s)
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
Date Issued
2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
AbstractThe 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.
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1038/s41467-021-23857-8
