Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.
Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.
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作者：
在禁食期间，哺乳动物通过刺激肝脏糖异生来维持血糖的动态平衡。循环中的高血糖素(GLU)和肾上腺素的升高触发了cAMP介导的CREB的磷酸化和CRTC2的去磷酸化。尽管潜在的机制尚不清楚，但肝脏的糖异生也受到生物钟的调节，生物钟协调葡萄糖代谢与外部环境的变化。在这里，我们展示了禁食期间的Creb活性是由隐花色素(Cry1和Cry2)调节的，这是时钟的核心成分，在肝脏中有节奏地表达。CRY在昼夜过渡期间升高，当它通过阻断GLU介导的细胞内cAMP浓度的增加和PKA介导的CREB的磷酸化而降低空腹糖异生基因的表达时。在生化重建研究中，我们发现Cry可抑制G蛋白偶联受体(GPCR)激活后cAMP的积聚，但不能抑制腺苷环化酶的直接激活剂Forsklin。CRY似乎通过与Gsα的相互作用直接调节gpr的活性。由于肝脏过表达Cry可降低胰岛素抵抗db/db小鼠的血糖浓度并改善胰岛素敏感性，我们的结果表明，增强Cry活性的化合物可能为II型糖尿病患者提供治疗益处。
During fasting, mammals maintain glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon (GLU) and epinephrine trigger the cAMP mediated phosphorylation of Creb and dephosphorylation of the Creb coactivator Crtc2. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Here we show that Creb activity during fasting is modulated by Cryptochromes (Cry1 and Cry2), core components of the clock that are rhythmically expressed in the liver. Cry was elevated during the night/day transition, when it reduced fasting gluconeogenic gene expression by blocking GLU-mediated increases in intracellular cAMP concentrations and in the PKA-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry inhibited accumulation of cAMP in response to G protein coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry appeared to modulate GPCR activity directly through interaction with Gsα . As hepatic over-expression of Cry lowered blood glucose concentrations and improved insulin sensitivity in insulin resistant db/db mice, our results suggest that compounds which enhance Cry activity may provide therapeutic benefit to individuals with type II diabetes.
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DOI：
10.1126/science.1152506
发表时间：
2008-05-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Neill JS;Maywood ES;Chesham JE;Takahashi JS;Hastings MH
通讯作者：
Hastings MH
影响因子：
64.8
作者：
Ueda, HR;Chen, WB;Hashimoto, S
通讯作者：
Hashimoto, S
影响因子：
2.1
作者：
Sanada, K;Harada, Y;Fukada, Y
通讯作者：
Fukada, Y
DOI：
10.1073/pnas.0408936102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Zhang, XQ;Smith, DL;Kazantsev, AG
通讯作者：
Kazantsev, AG
影响因子：
30.8
作者：
Sato, TK;Yamada, RG;Hogenesch, JB
通讯作者：
Hogenesch, JB