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- Title
A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism.
- 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
- 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.
- Subjects
GLUCOSE metabolism; RAPAMYCIN; TYPE 2 diabetes; METABOLIC regulation; GENE expression profiling; METABOLIC disorders
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-14323-y