The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Med. 2012 Feb 19;18(3):388-95. doi: 10.1038/nm.2686.
Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.
大量数据支持这样一种观点，即叉头框 O1（Foxo1）在禁食期间驱动肝脏转录程序，然后在进食后被胸腺瘤病毒原癌基因 1（Akt）抑制。在这里，我们表明，肝脏中 Akt1 和 Akt2 缺失的小鼠对葡萄糖不耐受，胰岛素抵抗，并且对肝脏进食的转录反应有缺陷。这些缺陷在同时缺失 Foxo1 的情况下得到了纠正。值得注意的是，在 Akt 和 Foxo1 都缺失的情况下，小鼠能够很好地适应禁食和进食状态，并且胰岛素能够正常地抑制肝葡萄糖产生。基因表达分析显示，肝脏中 Akt 的缺失导致 Foxo1 依赖性基因表达的组成性激活，但再次同时缺失 Foxo1 恢复了餐后调节，防止了 Akt 缺失导致的对营养摄入的代谢反应的抑制。这些结果与 Akt 是胰岛素信号适当传递所必需的中间物的经典肝脏代谢模型不一致。相反，它们表明肝脏 Akt 的主要作用是抑制 Foxo1 的活性，并且在没有 Foxo1 的情况下，Akt 在体内胰岛素和营养物质介导的肝脏代谢调节中在很大程度上是可有可无的。
