A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Article number | 644 |
Journal | Nature Communications |
Volume | 11 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2020 |
Externally published | Yes |
- Aged, Animals, Diabetes Mellitus, Type 2/genetics, Glucose/metabolism, Humans, Liver/metabolism, MafG Transcription Factor/genetics, Male, Mice, Middle Aged, Obesity/genetics, RNA, Long Noncoding/genetics, RNA, Messenger/genetics, Repressor Proteins/genetics, TOR Serine-Threonine Kinases/genetics
Research areas
ID: 389913596