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

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, wh...

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Published in:	Nature communications Vol. 11; no. 1; p. 644
Main Authors:	Pradas-Juni, Marta, Hansmeier, Nils R., Link, Jenny C., Schmidt, Elena, Larsen, Bjørk Ditlev, Klemm, Paul, Meola, Nicola, Topel, Hande, Loureiro, Rute, Dhaouadi, Ines, Kiefer, Christoph A., Schwarzer, Robin, Khani, Sajjad, Oliverio, Matteo, Awazawa, Motoharu, Frommolt, Peter, Heeren, Joerg, Scheja, Ludger, Heine, Markus, Dieterich, Christoph, Büning, Hildegard, Yang, Ling, Cao, Haiming, Jesus, Dario F. De, Kulkarni, Rohit N., Zevnik, Branko, Tröder, Simon E., Knippschild, Uwe, Edwards, Peter A., Lee, Richard G., Yamamoto, Masayuki, Ulitsky, Igor, Fernandez-Rebollo, Eduardo, Vallim, Thomas Q. de Aguiar, Kornfeld, Jan-Wilhelm
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 31-01-2020 Nature Publishing Group Nature Portfolio
Subjects:	38/91 631/208/4041/3196 631/337/2019 631/337/384/2568 692/163/2743/393 Aged Animals Blood glucose Chemoreception Deprivation Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Disease control Gene expression Glucose Glucose - metabolism Hepatocytes Homeostasis Humanities and Social Sciences Humans Hyperglycemia Insulin Liver - metabolism MafG Transcription Factor - genetics MafG Transcription Factor - metabolism Male Mammals Metabolic disorders Metabolism Mice Middle Aged Mouse devices multidisciplinary Nutrients Obesity Obesity - genetics Obesity - metabolism Rapamycin Repressor Proteins - genetics Repressor Proteins - metabolism RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism RNA-mediated interference Science Science (multidisciplinary) TOR protein TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-14323-y