2. Academic Validation
  3. Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling

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

  • Nat Commun. 2021 Jun 16;12(1):3660. doi: 10.1038/s41467-021-23857-8.
Celia de la Calle Arregui 1,  Ana Belén Plata-Gómez 1,  Nerea Deleyto-Seldas 1,  Fernando García 2,  Ana Ortega-Molina 1,  Julio Abril-Garrido 1,  Elena Rodriguez 3,  Ivan Nemazanyy 4,  Laura Tribouillard 5 6,  Alba de Martino 7,  Eduardo Caleiras 7,  Ramón Campos-Olivas 8,  Francisca Mulero 9,  Mathieu Laplante 5 6,  Javier Muñoz 2,  Mario Pende 10,  Guadalupe Sabio 3,  David M Sabatini 11 12 13 14 15,  Alejo Efeyan 16 17 18
Affiliations

Affiliations

  • 1 Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2 Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 3 Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 4 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France.
  • 5 Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval, Québec, QC, Canada.
  • 6 Centre de recherche sur le cancer de l'Université Laval, Université Laval, Québec, QC, Canada.
  • 7 Histopathology Unit. Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 8 Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 9 Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 10 Institut Necker Enfants Malades, INSERM U1151, Université de Paris, Paris, France.
  • 11 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, USA.
  • 12 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
  • 13 David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
  • 14 Broad Institute, Seven Cambridge Center, Cambridge, MA, USA.
  • 15 Howard Hughes Medical Institute, MIT, Cambridge, MA, USA.
  • 16 Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. [email protected].
  • 17 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, USA. [email protected].
  • 18 Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. [email protected].
PMID: 34135321 DOI: 10.1038/s41467-021-23857-8
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.

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