Functional Genomics and Metabolism Unit, Department for Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany.
Nat Commun. 2020 Jan 31;11(1):644. doi: 10.1038/s41467-020-14323-y.
Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease.
肥胖和 2 型糖尿病是全球性的紧急情况，长链非编码 RNA（lncRNA）是代谢中具有难以捉摸功能的调节转录物。在这里，我们表明，在饮食诱导的肥胖（DIO）和再喂养期间，大量的 lncRNA，但不是蛋白质编码的 mRNA，受到抑制，而营养剥夺诱导了小鼠肝脏中的 lncRNA。同样，糖尿病患者的 lncRNA 也会丢失。lncRNA 启动子分析、全局染色质分析和功能获得分析证实，DIO 期间 MAFG 信号的增加抑制了 lncRNA 的表达。在小鼠肝细胞和肥胖小鼠中沉默 Mafg 会引发类似于禁食的基因表达谱，改善葡萄糖代谢，解除 lncRNA 的抑制作用，并损害雷帕霉素靶蛋白（mTOR）的激活。我们发现肥胖抑制的 LincIRS2 受 MAFG 控制，并观察到遗传和 RNAi 介导的 LincIRS2 缺失会导致瘦小鼠的血糖升高、胰岛素抵抗和葡萄糖输出异常。总之，我们确定了一个 MAFG-lncRNA 轴，它在健康和代谢疾病中控制肝脏葡萄糖代谢。
