Physiological and pathological changes in glucose regulate brain akt and glycogen synthase kinase-3
Physiological and pathological changes in glucose regulate brain akt and glycogen synthase kinase-3
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DOI：
10.1074/jbc.m508824200
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发表时间：
2005-12-02
影响因子：
4.8
通讯作者：
Jope, RS
中科院分区：
文献类型：
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作者：
Clodfelder-Miller, B;De Sarno, P;Jope, RS
胰岛素可以调节外周组织中Akt和糖原合成酶激酶-3(GSK3)的磷酸化和活性，但在大脑中，这一信号通路在体内是如何调节的，以及它是否受到糖尿病的影响，目前还不清楚。我们发现Akt和GSK3对葡萄糖很敏感，因为在非糖尿病小鼠的大脑皮层和海马区，Akt和GSK3的磷酸化程度是非糖尿病小鼠的几倍，这是因为空腹减少和葡萄糖给药增加了几倍。给予链脲佐菌素(3天)后，脑组织Akt和GSK3的磷酸化水平也增加，导致血糖升高和血胰岛素耗竭，表明即使在胰岛素缺乏的情况下，也受到葡萄糖供应的调节。附睾脂Akt和GSK3的磷酸化及活性变化与脑组织相反。链脲佐菌素诱导的高血糖和脑内Akt和GSK3磷酸化的增加可通过胰岛素降低血糖而被逆转。在链脲佐菌素和db/db胰岛素抵抗小鼠4周后，长期高血糖也增加了大脑Akt和GSK3的磷酸化。因此，Akt-GSK3信号通路在小鼠体内受到调节，以响应胰岛素和葡萄糖的生理和病理变化。
Insulin regulates the phosphorylation and activities of Akt and glycogen synthase kinase-3 ( GSK3) in peripheral tissues, but in the brain it is less clear how this signaling pathway is regulated in vivo and whether it is affected by diabetes. We found that Akt and GSK3 are sensitive to glucose, because fasting decreased and glucose administration increased by severalfold the phosphorylation of Akt and GSK3 in the cerebral cortex and hippocampus of non-diabetic mice. Brain Akt and GSK3 phosphorylation also increased after streptozotocin administration ( 3 days), which increased blood glucose and depleted blood insulin, indicating regulation by glucose availability even with deficient insulin. Changes in Akt and GSK3 phosphorylation and activities in epididymal fat were opposite to those of brain after streptozotocin treatment. Streptozotocin-induced hyperglycemia and increased brain Akt and GSK3 phosphorylation were reversed by lowering blood glucose with insulin administration. Long term hyperglycemia also increased brain Akt and GSK3 phosphorylation, both 4 weeks after streptozotocin and in db/db insulin-resistant mice. Thus, the Akt-GSK3 signaling pathway is regulated in mouse brain in vivo in response to physiological and pathological changes in insulin and glucose.