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

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Pradas-Juni M., Hansmeier N. R., Link J. C., Schmidt E., Larsen B. D., Klemm P., ...More

NATURE COMMUNICATIONS, vol.11, no.1, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 11 Issue: 1
  • Publication Date: 2020
  • Doi Number: 10.1038/s41467-020-14323-y
  • Journal Name: NATURE COMMUNICATIONS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Agricultural & Environmental Science Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Geobase, INSPEC, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Dokuz Eylül University Affiliated: No

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.