The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
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DOI：
10.1038/nature03967
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发表时间：
2005-10-20
期刊：
影响因子：
64.8
通讯作者：
Montminy, M
中科院分区：
文献类型：
--
作者：
Koo, SH;Flechner, L;Montminy, M
葡萄糖稳态由激素如胰岛素和胰高血糖素系统调节，并在细胞水平上由能量状态调节。胰高血糖素通过环腺苷酸诱导因子CREB（CRE结合蛋白）刺激促血管生成基因的转录，从而在禁食期间增强肝脏的葡萄糖输出。然而，当细胞ATP水平较低时，能量敏感激酶AMPK通过一种未知的机制抑制肝再生。在这里，我们表明，激素和能量感应途径的辅激活剂TORC 2（调节CREB活性2的换能器），以调节葡萄糖输出。在进食条件下被隔离在细胞质中，TORC 2被去磷酸化并转运到细胞核，在那里它响应于禁食刺激而增强CREB依赖性转录。相反，激活AMPK的信号通过促进TORC 2磷酸化并阻断其核积累来减弱致凋亡程序。2型糖尿病患者经常表现出空腹高血糖症，这是由于代谢产物的增加;增强TORC 2磷酸化的化合物可能在这种情况下提供治疗益处。
Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.