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

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 RagA^GTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagA^GTP 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 RagA^GTP mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are p

SUBMITTER: de la Calle Arregui C 

PROVIDER: S-EPMC8209044 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature