Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice.
Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice.
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DOI：
10.3892/ijmm.18.3.433
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发表时间：
2006-09
影响因子：
5.4
通讯作者：
Hisanori Aoyama;H. Daitoku;A. Fukamizu
中科院分区：
文献类型：
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作者：
Hisanori Aoyama;H. Daitoku;A. Fukamizu
由进食或禁食介导的营养反应在控制致炎基因表达中起重要作用，例如葡萄糖-6-磷酸酶（G6 β）和磷酸烯醇式丙酮酸羧化酶（PEPCK）。FOXO家族的叉头转录因子Foxo 1（小鼠FOXO 1）是一种关键的调节因子，可刺激细胞核中促凋亡基因的表达，但被Akt（也称为蛋白激酶B; PK B）磷酸化，并在胰岛素应答时易位至细胞质。尽管胰岛素的细胞信号传导通过Akt依赖性磷酸化抑制Foxo 1功能已被广泛接受，但通过营养反应（包括进食或禁食）调节Foxo 1功能的分子机制在体内仍不清楚。我们使用对照C57 BL/6和糖尿病db/db小鼠研究了Akt介导的Foxo 1磷酸化和肝脏易位的营养变化的后果。我们发现，喂食促进Foxo 1的磷酸化和核排斥，而禁食则抵消了C57 BL/6小鼠。值得注意的是，db/db小鼠表现出组成性磷酸化，但占主导地位的核积累的Foxo 1，即使CREB磷酸化通常发生在禁食状态。此外，与C57 BL/6小鼠相反，db/db小鼠在进食期间G6 β、PEPCK和PGC-1 α基因的表达没有下调。因此，我们认为，Foxo 1通过Akt依赖性磷酸化的准确调节是需要生理适应不同的营养状态。
The nutrient response mediated by feeding or fasting plays an important role in controlling gluconeogenic gene expression such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK). The FOXO family of forkhead transcription factor Foxo1 (mouse FOXO1) is a key regulator that stimulates the expression of gluconeogenic genes in the nucleus but is phosphorylated by Akt (also known as protein kinase B; PKB) and translocated to the cytoplasm in response to insulin. Although it has been widely accepted that the cellular signaling of insulin represses Foxo1 function through Akt-dependent phosphorylation, the molecular mechanism behind the modulation of Foxo1 function by nutrient responses, including feeding or fasting, remains unknown in vivo. We investigated the consequences of the nutritional changes in Akt-mediated Foxo1 phosphorylation and translocation in the liver using control C57BL/6 and diabetic db/db mice. We found that feeding promotes the phosphorylation and nuclear exclusion of Foxo1, whereas fasting counteracted them in C57BL/6 mice. Notably, db/db mice exhibited constitutive phosphorylation but dominant nuclear accumulation of Foxo1, even though CREB phosphorylation usually occurred in the fasted status. Furthermore, in contrast to C57BL/6 mice, the expression of G6Pase, PEPCK and PGC-1alpha genes during feeding was not down-regulated in db/db mice. Thus, we suggest that the accurate regulation of Foxo1 via Akt-dependent phosphorylation is required for physiological adaptation to different nutritional statuses.