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

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.

• Authors: 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 Dieterich, Hildegard 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
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 644 (01 31 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32005828 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• MAFG protein, human
• MafG Transcription Factor
• Mafg protein, mouse
• RNA, Long Noncoding
• RNA, Messenger
• Repressor Proteins
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Aged
• Animals
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Glucose (metabolism)
• Humans
• Liver (metabolism)
• MafG Transcription Factor (genetics, metabolism)
• Male
• Mice
• Middle Aged
• Obesity (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)