Tissues may respond differently to a particular stimulus if they have been previously exposed to that same stimulus. Here we tested the hypothesis that a strong metabolic stimulus such as fasting may influence the hepatic response to a subsequent fast and thus elicit a memory effect. Overnight fasting in mice significantly increased plasma free fatty acids, glycerol, β-hydroxybutyrate and liver triglycerides, and decreased plasma glucose, plasma triglycerides, and liver glycogen levels. In addition, fasting dramatically changed the liver transcriptome, upregulating genes involved in gluconeogenesis and in uptake, oxidation, storage, and mobilization of fatty acids, and downregulating genes involved in fatty acid synthesis, fatty acid elongation/desaturation, and cholesterol synthesis. Fasting also markedly impacted the liver metabolome, causing a decrease in the levels of numerous amino acids, glycolytic intermediated, TCA cycle intermediates, and nucleotides. However, these fasting-induced changes were unaffected by two previous overnight fasts. Also, no significant effect was observed of prior fasting on glucose tolerance. Finally, analysis of the effect of fasting on the transcriptome in hepatocyte humanized mouse livers indicated modest similarity in gene regulation in mouse and human liver cells. In general, genes involved in metabolic pathways were up- or downregulated to a lesser extent in human liver cells than mouse liver cells. In conclusion, we found that previous exposure to fasting in mice did not influence the hepatic response to a subsequent fast, arguing against the concept of metabolic memory in the liver. Our data provide a useful resource for the study of liver metabolism during fasting.

中文翻译：

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探索肝脏对禁食反应的代谢记忆

如果组织之前曾接触过相同的刺激，则它们对特定刺激的反应可能会有所不同。在这里，我们测试了一个假设，即禁食等强烈的代谢刺激可能会影响肝脏对随后禁食的反应，从而引发记忆效应。小鼠隔夜禁食显着增加血浆游离脂肪酸、甘油、β-羟基丁酸和肝甘油三酯，并降低血浆葡萄糖、血浆甘油三酯和肝糖原水平。此外，禁食显着改变了肝脏转录组，上调了参与糖异生和脂肪酸摄取、氧化、储存和动员的基因，并下调了参与脂肪酸合成、脂肪酸延长/去饱和和胆固醇合成的基因。禁食也显着影响肝脏代谢组，导致许多氨基酸、糖酵解中间体、TCA 循环中间体和核苷酸的水平下降。然而，这些禁食引起的变化不受之前两次隔夜禁食的影响。此外，未观察到事先禁食对葡萄糖耐量的显着影响。最后，对禁食对肝细胞人源化小鼠肝脏转录组影响的分析表明，小鼠和人类肝细胞的基因调控具有适度的相似性。一般来说，与小鼠肝细胞相比，人肝细胞中参与代谢途径的基因上调或下调的程度要小。总之，我们发现小鼠之前的禁食暴露不会影响肝脏对随后禁食的反应，这与肝脏代谢记忆的概念相悖。