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Keywords:

  • FoxO6;
  • gluconeognesis;
  • glucose metabolism;
  • liver;
  • type 2 diabetes
  • FoxO6,葡萄糖异生,葡萄糖代谢,肝脏,2型糖尿病

Abstract

The forkhead box O (FoxO) subfamily has four members, namely FoxO1, FoxO3, FoxO4, and FoxO6. Unlike the other three members of the FoxO family, FoxO6 has garnered considerably less attention because of earlier reports that FoxO6 expression was limited to the brain. Recent data indicate that FoxO6 is produced in the liver of both rodents and humans. Hepatic FoxO6 activity, which remains at low basal levels in fed states, is markedly induced in fasted mice. FoxO6 activity becomes abnormally higher in the liver of mice with dietary obesity or type 2 diabetes (T2D). Genetically engineered mice with elevated FoxO6 activity in the liver exhibit prediabetes, culminating in the development of glucose intolerance, fasting hyperglycemia, and hyperinsulinemia. Conversely, inhibition of FoxO6 activity in the insulin-resistant liver results in a reduction in fasting hyperglycemia, contributing to the amelioration of hyperinsulinemia in T2D mice. These new data suggest that FoxO6 is an important regulator of hepatic glucose metabolism in response to insulin or physiological cues. Insulin inhibits FoxO6 activity by promoting its phosphorylation and disabling its activity in the nucleus without altering its subcellular distribution via a mechanism that is distinct from other members of the FoxO subfamily. In this article, we comprehensively review the role of FoxO6 in glucose metabolism in health and disease. We also address whether FoxO6 dysregulation is a contributing factor for the pathogenesis of fasting hyperglycemia and discuss whether FoxO6 is a potential therapeutic target for improving fasting hyperglycemia in T2D.

摘要

叉头框O(FoxO)亚科有4个成员,亦即FoxO1、FoxO3、FoxO4与FoxO6。与其他3个FoxO家族成员不一样的是,因为先前有研究报告了FoxO6仅在大脑中表达,所以很少有人关注FoxO6。最近的数据表明,在啮齿类以及人类的肝脏中都能够产生FoxO6。小鼠在进食状态下肝脏中的FoxO6活性维持在一个较低的基础水平,而禁食可以显著诱导产生FoxO6。喂养的肥胖或者2型糖尿病(T2D)小鼠肝脏中的FoxO6活性异常升高。肝脏FoxO6活性升高的遗传工程小鼠出现了糖尿病前期状态,最后发展成葡萄糖耐量异常、空腹高血糖以及高胰岛素血症。相反,在有胰岛素抵抗的肝脏中抑制FoxO6的活性可导致T2D小鼠的空腹高血糖下降,并且有利于高胰岛素血症的改善。这些新的数据表明,在肝脏对胰岛素或者生理学信号起反应的葡萄糖代谢过程中,FoxO6是一个重要的调节因素。胰岛素通过促进FoxO6的磷酸化来抑制它的活性,并且在细胞核中使它失活,但是并没有改变它的亚细胞分布,这与FoxO亚科中其他成员的作用机制有所不同。在这篇文章中,我们全面地回顾了FoxO6在健康人以及患者的葡萄糖代谢中的作用。我们讨论了FoxO6失调在空腹高血糖的发病机制中是否是一个促进因素,并且讨论了为了改善T2D患者的空腹高血糖,是否要将FoxO6作为一个潜在的治疗目标。