Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Am J Physiol Endocrinol Metab. 2014 Jan 15;306(2):E197-209. doi: 10.1152/ajpendo.00202.2013. Epub 2013 Dec 3.
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.
营养过剩与肥胖、胰岛素抵抗和 2 型糖尿病的发生有关。然而，在存在过量营养物质的情况下，导致胰岛素抵抗的潜在机制尚不完全清楚。我们研究了 AMP 激活的蛋白激酶（AMPK）的激活是否可以防止高蛋白饮食（HPD）和过量氨基酸摄入引起的肝胰岛素抵抗。暴露于过量氨基酸的 HepG2 细胞会减少 AMPK 磷酸化，上调 Notch1 表达，并损害胰岛素刺激的 Akt Ser(473)和胰岛素受体底物-1（IRS-1）Tyr(612)磷酸化。Notch1 的抑制可防止氨基酸引起的胰岛素抵抗，同时减少 Rbp-Jk、Hairy 和 Enhancer of Split-1、forkhead box O1 的表达。从机制上讲，过量的氨基酸激活了 mTORC1 信号，然后通过激活信号转导和转录激活因子 3（STAT3）正向调节 Notch1 的表达。二甲双胍激活 AMPK 可抑制 mTORC1-STAT3 信号，从而防止过量氨基酸损害胰岛素信号。最后，HPD 喂养抑制 AMPK 活性，激活 mTORC1/STAT3/Notch1 信号通路，并诱导胰岛素抵抗。长期给予二甲双胍或雷帕霉素可抑制 HPD 激活的 mTORC1/STAT3/Notch1 信号通路，并防止肝胰岛素抵抗。我们的结论是，过度活跃的 mTORC1 信号上调 Notch1 表达是在存在过量氨基酸的情况下发生肝胰岛素抵抗的一个重要事件。AMPK 的激活通过抑制 mTORC1/STAT3/Notch1 信号通路来防止氨基酸诱导的胰岛素抵抗。
