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• W2000844923 abstract "Nutrient overload is associated with the development of obesity, insulin resistance, and type 2 diabetes. However, the underlying mechanisms for developing insulin resistance in the presence of excess nutrients are incompletely understood. We investigated whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic insulin resistance that is induced by the consumption of a high-protein diet (HPD) and the presence of excess amino acids. Exposure of HepG2 cells to excess amino acids reduced AMPK phosphorylation, upregulated Notch1 expression, and impaired the insulin-stimulated phosphorylation of Akt Ser 473 and insulin receptor substrate-1 (IRS-1) Tyr 612 . Inhibition of Notch1 prevented amino acid-induced insulin resistance, which was accompanied by reduced expression of Rbp-Jk, hairy and enhancer of split-1, and forkhead box O1. Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). Activation of AMPK by metformin inhibited mTORC1-STAT3 signaling, thereby preventing excess amino acid-impaired insulin signaling. Finally, HPD feeding suppressed AMPK activity, activated mTORC1/STAT3/Notch1 signaling, and induced insulin resistance. Chronic administration of either metformin or rapamycin inhibited the HPD-activated mTORC1/STAT3/Notch1 signaling pathway and prevented hepatic insulin resistance. We conclude that the upregulation of Notch1 expression by hyperactive mTORC1 signaling is an essential event in the development of hepatic insulin resistance in the presence of excess amino acids. Activation of AMPK prevents amino acid-induced insulin resistance through the suppression of the mTORC1/STAT3/Notch1 signaling pathway." @default.
• W2000844923 created "2016-06-24" @default.
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• W2000844923 date "2014-01-15" @default.
• W2000844923 modified "2023-10-17" @default.
• W2000844923 title "Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids" @default.
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• W2000844923 doi "https://doi.org/10.1152/ajpendo.00202.2013" @default.
• W2000844923 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3920006" @default.
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