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.
Highlights
The mechanistic target of rapamycin complex 1 integrates cellular nutrient signaling and hormonal cues to control metabolism
The signal transduction cascade emanating from insulin binding its receptor at the plasma membrane involves the activation of PI3K and AKT, which leads to the inhibitory phosphorylation of the tuberous sclerosis complex (TSC), itself a GTPase activating protein (GAP) toward Ras homology enriched in brain (RHEB), responsible for direct binding and kinase activation of mTORC13
We reasoned that enriching the RagAGTP strain to the 129/Sv background could result in a milder phenotype that would allow partial neonatal survival
Summary
The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. TSC1/2 knock-out mice die embryonically with supra-physiological mTORC1 activity, and tissue-specific models of deregulated hormonal signaling to mTORC1 have taught us its relevance in coordinating fasting-feeding responses, and in driving pathological growth[7,8,9,10]. To interrogate on the physiological perturbations caused by systemic chronic elevation in nutrient signaling we have previously generated a gain-of-function model of nutrient signaling to mTORC1 with knock-in mice expressing a GTP-bound, constitutively-active form of RagA under endogenous control of expression[15]. RagAGTP/GTP mice developed normally but succumbed within hours after birth due to a profound metabolic crisis that manifested with decreased circulating levels of amino acids and hypoglycaemia This metabolic crisis was caused by the inability of cells with constitutive nutrient signaling to inhibit mTORC1 during the early neonatal starvation period and, by an impairment in the execution of nutrient-recycling autophagy[15]. Adult RagAGTP mice allow for the interrogation of the consequences of full-body constitutive mTORC1 activity after development, as other genetic tools of activation of mTORC1 in mice (such as loss of the TSC complex) result in developmental lethality[4]
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