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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity
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Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity

机译：靶向破坏CREB共激活因子Crtc2可提高胰岛素敏感性

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摘要

Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2~(-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.
机译：在禁食条件下，胰高血糖素循环浓度的增加通过CREB共激活因子CRTC2诱导的糖异生基因来维持葡萄糖稳态。肥胖患者的肝CRTC2活性升高，尽管该辅助因子对伴随胰岛素抵抗增加的贡献程度尚不清楚。在这里，我们显示，由于糖原异生程序的减弱，具有敲除CRTC2基因的小鼠的禁食中循环葡萄糖浓度降低。发现CRTC2部分通过N末端CREB结合域刺激肝脏基因表达，该域增强了对胰高血糖素的响应，相对于相关启动子，CREB的占有率更高。在饮食引起的肥胖的情况下，在CRTC2-（-/-）小鼠中删除编码CREB结合结构域的序列降低了循环血糖浓度并改善了胰岛素敏感性。我们的结果表明，减弱CREB-CRTC2途径的小分子可能为2型糖尿病患者提供治疗益处。

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  • 作者

    Yiguo Wang; Hiroshi Inoue; Kim Ravnskjaer; Kristin Viste; Nina Miller; Yi Liu; Susan Hedrick; Liliana Vera; Marc Montminy;

  • 作者单位

    Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

    rnSalk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, CA 92037;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    gluconeogenesis; obesity; CREB; CRTC2; insulin;

    机译：糖异生肥胖;CREB;CRTC2;胰岛素;

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