Santoleri Dominic, Lim Hee-Woong, Emmett Matthew J, Stoute Julian, Gavin Matthew J, Sostre-Colón Jaimarie, Uehara Kahealani, Welles Jaclyn E, Liu Kathy Fange, Lazar Mitchell A, Titchenell Paul M
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA.
Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA.
iScience. 2022 May 16;25(6):104410. doi: 10.1016/j.isci.2022.104410. eCollection 2022 Jun 17.
The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA , whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.
胰岛素反应性Akt和FoxO1信号轴是肝脏对营养摄入转录反应的关键调节因子。在此，我们使用全局连续转录测序（GRO-seq）来测量禁食和重新喂食后的新生转录反应，并确定肝脏Akt和FoxO1信号在介导这种反应中的具体作用。我们鉴定出599个受进食调节的转录本以及6000多个增强子RNA（eRNA），并确定了它们对Akt和FoxO1信号的依赖性。此外，我们鉴定出几种受进食调节的长链非编码RNA（lncRNA），包括lncRNA ，其表达依赖于肝脏Akt-FoxO1轴。在缺乏肝脏Akt的小鼠中恢复 的表达可改善胰岛素敏感性并诱导葡萄糖激酶蛋白表达，这表明Akt对 的依赖性控制有助于葡萄糖激酶的翻译控制。更广泛地说，我们生成了一个独特的全基因组数据集，该数据集定义了响应营养可利用性的进食和Akt/FoxO1依赖性转录变化。
