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.
Link, Jenny; Pradas-Juni, Martha; Hansmeier, Nils R.; Schmidt, Elena; Ditlev Larsen, Bjørk; Klemm, Paul; Meola, Nicola; Topel, Hande; Loureiro, Rute; Dhaouadi, Ines; Kiefer, Christoph A.; Schwarzer, Robin; Khani, Sajjad; Oliverio, Matteo; Awazawa, Motoharu; Frommolt, Peter; Heeren, Joerg; Scheja, Ludger; Heine, Markus; Dieterich, Christoph; Büning, Hildegard; Yang, Ling; Cao, Haiming; De Jesus, Dario F.; Kulkarni, Rohit; Zevnik, Branko; Tröder, Simon E.; Knippschild, Uwe; Edwards, Peter A.; Lee, Richard G.; Yamamoto, Masayuki; Ulitsky, Igor; Fernandez-Rebollo, Eduardo; de Aguiar Vallim, Thomas Q.; and Kornfeld, Jan-Wilhelm, "A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism" (2020). Biology. 2.