Pradas-Juni, Marta, Hansmeier, Nils R., Link, Jenny C., Schmidt, Elena ORCID: 0000-0003-0829-1423, Larsen, Bjork Ditlev, Klemm, Paul ORCID: 0000-0002-5985-1737, Meola, Nicola, Topel, Hande ORCID: 0000-0001-5743-4019, Loureiro, Rute, Dhaouadi, Ines ORCID: 0000-0002-2762-6500, Kiefer, Christoph A., Schwarzer, Robin, Khani, Sajjad, Oliverio, Matteo, Awazawa, Motoharu, Frommolt, Peter ORCID: 0000-0002-1966-8014, Heeren, Joerg, Scheja, Ludger, Heine, Markus, Dieterich, Christoph, Buening, Hildegard, Yang, Ling, Cao, Haiming, De Jesus, Dario F., Kulkarni, Rohit N., Zevnik, Branko ORCID: 0000-0001-7845-9522, Troeder, Simon E., Knippschild, Uwe, Edwards, Peter A., Lee, Richard G., Yamamoto, Masayuki, Ulitsky, Igor, Fernandez-Rebollo, Eduardo, Vallim, Thomas Q. de Aguiar and Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442 (2020). A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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. Despite widespread transcription of LncRNA in mammalian systems, their contribution to metabolic homeostasis at the cellular and tissue level remains elusive. Here Pradas-Juni et al. describe a transcription factor-LncRNA pathway that couples hepatocyte nutrient sensing to regulation of glucose metabolism in mice.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pradas-Juni, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansmeier, Nils R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Link, Jenny C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ElenaUNSPECIFIEDorcid.org/0000-0003-0829-1423UNSPECIFIED
Larsen, Bjork DitlevUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klemm, PaulUNSPECIFIEDorcid.org/0000-0002-5985-1737UNSPECIFIED
Meola, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Topel, HandeUNSPECIFIEDorcid.org/0000-0001-5743-4019UNSPECIFIED
Loureiro, RuteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dhaouadi, InesUNSPECIFIEDorcid.org/0000-0002-2762-6500UNSPECIFIED
Kiefer, Christoph A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarzer, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khani, SajjadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliverio, MatteoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Awazawa, MotoharuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frommolt, PeterUNSPECIFIEDorcid.org/0000-0002-1966-8014UNSPECIFIED
Heeren, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheja, LudgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heine, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieterich, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buening, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, LingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cao, HaimingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jesus, Dario F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kulkarni, Rohit N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zevnik, BrankoUNSPECIFIEDorcid.org/0000-0001-7845-9522UNSPECIFIED
Troeder, Simon E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edwards, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Richard G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yamamoto, MasayukiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ulitsky, IgorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Rebollo, EduardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vallim, Thomas Q. de AguiarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornfeld, Jan-WilhelmUNSPECIFIEDorcid.org/0000-0002-6802-4442UNSPECIFIED
URN: urn:nbn:de:hbz:38-347934
DOI: 10.1038/s41467-020-14323-y
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LONG NONCODING RNA; TRANSCRIPTION FACTOR; ACID SYNTHESIS; GENE; EXPRESSION; CHOLESTEROL; MECHANISMS; EVOLUTION; PROTEIN; ANNOTATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34793

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