Selective control of up-regulated and down-regulated genes by temporal patterns and doses of insulin
Selective control of up-regulated and down-regulated genes by temporal patterns and doses of insulin
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DOI：
10.1126/scisignal.aaf3739
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发表时间：
2016-11-22
影响因子：
7.3
通讯作者：
Kuroda, Shinya
中科院分区：
文献类型：
--
作者：
Sano, Takanori;Kawata, Kentaro;Kuroda, Shinya
进食后胰岛素的分泌短暂增加，导致循环浓度升高。禁食限制胰岛素分泌，导致循环中胰岛素浓度低。我们分析了肝癌FAO细胞中对不同时间模式和胰岛素剂量的转录反应，并鉴定了13个上调和16个下调的胰岛素反应基因（IRG）。上调的IRG比下调的IRG对胰岛素浓度的瞬时逐步或脉冲增加的反应更快，而下调的IRG在比刺激上调的IRG所需的胰岛素浓度更低的胰岛素浓度下受到抑制。将胰岛素反应分为两个阶段（i）胰岛素信号转导和（ii）转录和 mRNA 稳定性的数学模型表明，第一阶段是下调 IRG 的较快速阶段，而转录的第二阶段是上调 IRG 的较快速阶段。在FAO细胞中上调或下调的IRGs的一个子集在注射单剂量胰岛素的大鼠的肝脏中也受到类似的调节。因此，细胞不仅可以对胰岛素做出反应，而且还可以解释信号的强度和模式以产生不同的转录反应。这些结果提供了可能有助于治疗与异常胰岛素产生或组织反应性相关的肥胖和 2 型糖尿病的见解。
Secretion of insulin transiently increases after eating, resulting in a high circulating concentration. Fasting limits insulin secretion, resulting in a low concentration of insulin in the circulation. We analyzed transcriptional responses to different temporal patterns and doses of insulin in the hepatoma FAO cells and identified 13 up-regulated and 16 down-regulated insulin-responsive genes (IRGs). The up-regulated IRGs responded more rapidly than did the down-regulated IRGs to transient stepwise or pulsatile increases in insulin concentration, whereas the down-regulated IRGs were repressed at lower concentrations of insulin than those required to stimulate the up-regulated IRGs. Mathematical modeling of the insulin response as two stages-(i) insulin signaling to transcription and (ii) transcription and mRNA stability-indicated that the first stage was the more rapid stage for the down-regulated IRGs, whereas the second stage of transcription was the more rapid stage for the up-regulated IRGs. A subset of the IRGs that were up-regulated or down-regulated in the FAO cells was similarly regulated in the livers of rats injected with a single dose of insulin. Thus, not only can cells respond to insulin but they can also interpret the intensity and pattern of signal to produce distinct transcriptional responses. These results provide insight that may be useful in treating obesity and type 2 diabetes associated with aberrant insulin production or tissue responsiveness.