Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2
Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2
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DOI：
10.1074/jbc.m115.679266
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发表时间：
2015-10-23
影响因子：
4.8
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
--
作者：
Hogan, Meghan F.;Ravnskjaer, Kim;Montminy, Marc
在禁食条件下，胰高血糖素循环浓度的增加通过诱导肝脏糖异生来维持葡萄糖稳态。肝细胞中 cAMP 通路的触发通过 PKA 介导的 CREB 磷酸化和 cAMP 调节的 CREB 共激活剂 CRTC2 和 CRTC3 去磷酸化来刺激糖异生程序。与此同时，循环胰岛素的减少也会通过叉头转录因子 FOXO1 的去磷酸化和激活来增加糖异生基因的表达。胰岛素抵抗导致肝脏糖异生增加，从而导致高血糖。然而，选择性激活肝脏 CREB/CRTC 通路是否足以引发其他组织的代谢变化尚不清楚。磷酸化缺陷且因此具有组成型活性的 CRTC2S171,275A 蛋白的适度肝脏表达在禁食和进食条件下增加了糖异生基因的表达。 CRTC2S(171,275)A 表达小鼠的循环葡萄糖浓度持续升高，导致循环胰岛素浓度代偿性增加，从而增强 FOXO1 磷酸化。尽管伴随着 FOXO1 活性的降低，CRTC2S(171,275)A 小鼠中肝脏糖异生基因表达仍然升高，这表明肝脏中 CRTC2 活性的长期增加确实足以促进肝脏胰岛素抵抗并破坏葡萄糖稳态。
Under fasting conditions, increases in circulating concentrations of glucagon maintain glucose homeostasis via the induction of hepatic gluconeogenesis. Triggering of the cAMP pathway in hepatocytes stimulates the gluconeogenic program via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia. Whether selective activation of the hepatic CREB/CRTC pathway is sufficient to trigger metabolic changes in other tissues is unclear, however. Modest hepatic expression of a phosphorylation-defective and therefore constitutively active CRTC2S171,275A protein increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S(171,275)A-expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S(171,275)A mice, demonstrating that chronic increases inCRTC2activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis.