Short‐term High Fat Diet Feeding Leads to Resistance of Hepatic mTORC1 Signaling to Stimulation by Amino Acids

A major complication of obesity is development of non‐alcoholic fatty liver disease (NAFLD). However, although many of the phenotypic and genotypic characteristics of the disease have been identified, the molecular triggering events that initiate it are undefined. In the present study, the effect of short‐term (i.e. 蠄 2 wk) consumption of a high‐fat diet (HFD) on changes in signaling through the protein kinase mTOR in complex 1 (mTORC1) was assessed. In contrast to previous studies showing constitutive activation of mTORC1 in the liver of animals fed a HFD for four or more weeks, in the present study mTORC1 signaling was lower in fasted rats that had been fed a high fat compared to a control diet. Moreover, the stimulatory effect of re‐feeding fasted animals was blunted in animals consuming a HFD compared to controls. Repressed feeding‐induced activation of mTORC1 signaling was not due to insulin resistance. Instead, livers of rats fed a HFD exhibited resistance of mTORC1 to activation by amino acids. In support of this conclusion, the feeding‐induced association of the amino acid‐responsive Rag GTPases with mTORC1 was blunted in HFD‐fed rats compared to controls. Moreover, both basal and amino acid‐induced activation of mTORC1 signaling was significantly reduced in livers from HFD‐fed compared to control rats after perfusion in situ with medium containing amino acids at the concentrations found in the plasma of fasted rats (1X) or four times those concentrations. Overall, the results are consistent with the conclusion that consuming a high‐fat diet causes changes in the Rag signaling pathway that result in resistance to amino acid‐induced activation of mTORC1. (Supported by NIH grant DK13499)