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 DieterichHildegard 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*, Jan-Wilhelm Kornfeld

*Corresponding author for this work

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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.

Original languageEnglish
Article number644
JournalNature Communications
Volume11
Issue number1
ISSN2041-1723
DOIs
Publication statusPublished - 2020

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    Pradas-Juni, M., Hansmeier, N. R., Link, J. C., Schmidt, E., Larsen, B. D., Klemm, P., Meola, N., Topel, H., Loureiro, R., Dhaouadi, I., Kiefer, C. A., Schwarzer, R., Khani, S., Oliverio, M., Awazawa, M., Frommolt, P., Heeren, J., Scheja, L., Heine, M., ... Kornfeld, J-W. (2020). A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. Nature Communications, 11(1), [644]. https://doi.org/10.1038/s41467-020-14323-y