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Nat Commun. 2020 Jan 31;11(1):644. doi: 10.1038/s41467-020-14323-y.

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

Author information

1
Functional Genomics and Metabolism Unit, Department for Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
2
Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany.
3
Cologne Cluster of Excellence-Cellular Stress Responses in Ageing-associated Diseases (CECAD), Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
4
Department of Biological Chemistry, University of California, Los Angeles (UCLA), 650 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
5
Department of Medicine, Division of Cardiology, UCLA, 650 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
6
Izmir Biomedicine and Genome Center (IBG), Mithatpasa Ave. 58/5, 35340, Izmir, Turkey.
7
Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Mithatpasa Ave. 1606, 35330, Izmir, Turkey.
8
Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
9
Department of Biochemistry and Molecular Cell Biology, Martinistraße 52, 20246, Hamburg, Germany.
10
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
11
Institute of Experimental Hematology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
12
Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD, 20892, USA.
13
Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
14
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, 02215, MA, USA.
15
CECAD in vivo Research Facility, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
16
Department of General and Visceral Surgery, University Hospital Ulm, Albert-Einstein Allee 93, 89081, Ulm, Germany.
17
IONIS Pharmaceuticals, Carlsbad, CA, 92010, USA.
18
Department of Medical Biochemistry, Tohoku Medical Megabank Organization, Sendai, 980-8573, Japan.
19
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 76100, Israel.
20
Department of Biological Chemistry, University of California, Los Angeles (UCLA), 650 Charles E. Young Drive South, Los Angeles, CA, 90095, USA. TVallim@mednet.ucla.edu.
21
Department of Medicine, Division of Cardiology, UCLA, 650 Charles E. Young Drive South, Los Angeles, CA, 90095, USA. TVallim@mednet.ucla.edu.
22
Functional Genomics and Metabolism Unit, Department for Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark. janwilhelmkornfeld@bmb.sdu.dk.
23
Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany. janwilhelmkornfeld@bmb.sdu.dk.
24
Cologne Cluster of Excellence-Cellular Stress Responses in Ageing-associated Diseases (CECAD), Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany. janwilhelmkornfeld@bmb.sdu.dk.

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.

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