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 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 () and Jan-Wilhelm Kornfeld ()
Additional contact information
Marta Pradas-Juni: University of Southern Denmark
Nils R. Hansmeier: Max Planck Institute for Metabolism Research
Jenny C. Link: University of California, Los Angeles (UCLA)
Elena Schmidt: Max Planck Institute for Metabolism Research
Bjørk Ditlev Larsen: University of Southern Denmark
Paul Klemm: Max Planck Institute for Metabolism Research
Nicola Meola: University of Southern Denmark
Hande Topel: University of Southern Denmark
Rute Loureiro: University of Southern Denmark
Ines Dhaouadi: Max Planck Institute for Metabolism Research
Christoph A. Kiefer: University of Southern Denmark
Robin Schwarzer: Medical Faculty, University of Cologne
Sajjad Khani: Max Planck Institute for Metabolism Research
Matteo Oliverio: Max Planck Institute for Metabolism Research
Motoharu Awazawa: Max Planck Institute for Metabolism Research
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
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)
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)
Jan-Wilhelm Kornfeld: University of Southern Denmark

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14323-y

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