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

Author

Listed:
  • Marta Pradas-Juni

    (University of Southern Denmark
    Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Nils R. Hansmeier

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Jenny C. Link

    (University of California, Los Angeles (UCLA)
    Division of Cardiology, UCLA)

  • Elena Schmidt

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Bjørk Ditlev Larsen

    (University of Southern Denmark)

  • Paul Klemm

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Nicola Meola

    (University of Southern Denmark)

  • Hande Topel

    (University of Southern Denmark
    Izmir Biomedicine and Genome Center (IBG)
    Dokuz Eylul University)

  • Rute Loureiro

    (University of Southern Denmark
    Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Ines Dhaouadi

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Christoph A. Kiefer

    (University of Southern Denmark)

  • Robin Schwarzer

    (Medical Faculty, University of Cologne)

  • Sajjad Khani

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Matteo Oliverio

    (Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

  • Motoharu Awazawa

    (Max Planck Institute for Metabolism Research
    Diabetes Research Center, Research Institute, National Center for Global Health and Medicine)

  • Peter Frommolt

    (Medical Faculty, University of Cologne)

  • Joerg Heeren

    (Department of Biochemistry and Molecular Cell Biology)

  • Ludger Scheja

    (Department of Biochemistry and Molecular Cell Biology)

  • Markus Heine

    (Department of Biochemistry and Molecular Cell Biology)

  • Christoph Dieterich

    (University Hospital Heidelberg)

  • Hildegard Büning

    (Institute of Experimental Hematology, Hanover Medical School)

  • Ling Yang

    (Cardiovascular Branch, National Heart Lung and Blood Institute
    Temple University)

  • Haiming Cao

    (Cardiovascular Branch, National Heart Lung and Blood Institute)

  • Dario F. De Jesus

    (Harvard Stem Cell Institute, Harvard Medical School)

  • Rohit N. Kulkarni

    (Harvard Stem Cell Institute, Harvard Medical School)

  • Branko Zevnik

    (University of Cologne)

  • Simon E. Tröder

    (University of Cologne)

  • Uwe Knippschild

    (University Hospital Ulm)

  • Peter A. Edwards

    (University of California, Los Angeles (UCLA)
    Division of Cardiology, UCLA)

  • Richard G. Lee

    (IONIS Pharmaceuticals)

  • Masayuki Yamamoto

    (Tohoku Medical Megabank Organization)

  • Igor Ulitsky

    (Weizmann Institute of Science)

  • Eduardo Fernandez-Rebollo

    (University of Southern Denmark)

  • Thomas Q. de Aguiar Vallim

    (University of California, Los Angeles (UCLA)
    Division of Cardiology, UCLA)

  • Jan-Wilhelm Kornfeld

    (University of Southern Denmark
    Max Planck Institute for Metabolism Research
    Medical Faculty, University of Cologne)

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.

Suggested Citation

  • 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 Schw, 2020. "A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14323-y
    DOI: 10.1038/s41467-020-14323-y
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