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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Marta Pradas-Juni
  • Nils R Hansmeier
  • Jenny C Link
  • Elena Schmidt
  • Bjørk Ditlev Larsen
  • Paul Klemm
  • Nicola Meola
  • 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-Rebollo
  • Thomas Q de Aguiar Vallim
  • Jan-Wilhelm Kornfeld

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
ISSN2041-1723
DOIs
Publication statusPublished - 2020
Externally publishedYes

    Research areas

  • Aged, Animals, Diabetes Mellitus, Type 2/genetics, Glucose/metabolism, Humans, Liver/metabolism, MafG Transcription Factor/genetics, Male, Mice, Middle Aged, Obesity/genetics, RNA, Long Noncoding/genetics, RNA, Messenger/genetics, Repressor Proteins/genetics, TOR Serine-Threonine Kinases/genetics

ID: 389913596