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

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 DieterichHildegard 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-Rebollo, Thomas Q.de Aguiar Vallim, Jan Wilhelm Kornfeld

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number644
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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