A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

• DOI: 10.1038/s41467-020-14323-y
• Publication Date: 2020-01-31T11:02:58Z
• Authors: Marta Pradas-Juni; Nils R. Hansmeier; Jenny C. Link; Elena Schmidt; Bjørk Ditlev Larsen; Paul Klemm; Nicola Meola; Hande Topel; Rute Loureiro; Ines Dhaouadi; Christoph A. Kiefer; Robin Schwarzer; Sajjad Khani; Matteo Oliverio; Motoharu Awazawa; Peter Frommolt; Joerg Heeren; Ludger Scheja; Markus Heine; Christoph Dieterich; Hildegard Büning; Ling Yang; Haiming Cao; Dario F. De Jesus; Rohit N. Kulkarni; Branko Zevnik; Simon E. Tröder; Uwe Knippschild; Peter A. Edwards; Richard G. Lee; Masayuki Yamamoto; Igor Ulitsky; Eduardo Fernandez...; Thomas Q. de Agui...; Jan-Wilhelm Kornfeld
• Keywords: MafG Transcription Factor; Male; 0301 basic medicine; 2. Zero hunger; Science; TOR Serine-Threonine Kinases; Q; Middle Aged; Article; Repressor Proteins; Mice; 03 medical and health sciences; Glucose; Diabetes Mellitus, Type 2; Liver; Animals; Humans; RNA, Long Noncoding; Obesity; RNA, Messenger; Aged

Obesity and type 2 diabetes mellitus are global emergencies long noncoding RNAs (lncRNAs) regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, repressed during diet-induced obesity (DIO) refeeding, whilst nutrient deprivation induced lncRNAs mouse liver. Similarly, lost diabetic humans. LncRNA promoter analyses, cistrome gain-of-function analyses confirm increased MAFG signaling DIO curbs lncRNA expression. Silencing Mafg hepatocytes obese mice elicits fasting-like gene expression profile, improves glucose metabolism, de-represses impairs mammalian target rapamycin (mTOR) activation. We find obesity-repressed LincIRS2 is controlled by observe genetic RNAi-mediated loss causes elevated blood glucose, insulin resistance aberrant output lean mice. Taken together, identify MAFG-lncRNA axis controlling hepatic metabolism health metabolic disease.