Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.

中文翻译：

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TSC复合物的丢失通过Dlk1-Dio3基因座miRNA的上调增强糖异生作用。

肝脏中肿瘤抑制性结节性硬化症复合物1（Tsc1）的丢失会促进糖异生和葡萄糖耐受不良。我们问这是否可以归因于小RNA的异常表达。我们在Tsc1基因敲除小鼠的肝脏上进行了小RNA测序，发现δ样同源物1（Dlk1）-脱碘酶I碘甲状腺素III型（Dio3）基因座的miRNA以mTORC1依赖性方式上调。在发育过程中持续的mTORC1信号传导阻止了CpG甲基化和Dlk1-Dio3基因座的沉默，从而增加了miRNA的转录。由Dlk1-Dio3基因座编码的miRNA的缺失减少了糖异生，葡萄糖不耐症和空腹血糖水平。因此，miRNA有助于在肝脏中TSC1丢失和mTORC1过度活化时观察到的代谢作用。此外，