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.

Highlights

  • Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs are regulatory transcripts with elusive functions in metabolism

  • To identify long noncoding RNAs (lncRNAs) that are implicated in the development of liver disease pathologies in diet-induced obesity (DIO), for instance insulin resistance, steatosis, and liver inflammation, 6-week-old C57BL/6N mice were fed a high-fat diet (HFD) or control diet (CD)

  • Performing Ingenuity Pathway Analysis (IPA) confirmed activation of transcription factor (TF) networks and signaling pathways known to be induced in the liver under anabolic/nutrient-rich conditions

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Summary

Introduction

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Remarkable for living in seemingly postgenomic times, we currently witness a paradigm shift in understanding our genomes and the information contained therein: multinational sequencing efforts like ENCODE6, FANTOM7, or NONCODE8, together with increasing RNA-Sequencing (RNA-Seq) capabilities and reduced costs, led to the intriguing discovery that, whereas only 1–2% of genomic information encodes protein-coding mRNAs, more than 70% of DNA is transcribed across developmental space and time[9,10] This led to the identification of thousands of microRNAs, and more recently, long noncoding RNAs (lncRNAs)[11,12] in mice and humans[13]. In vitro and in vivo loss of MAFG in hepatocytes controls glucose production, improves glucose metabolism during obesity, and induces lncRNAs, whereas MAFG gain of function represses hepatic lncRNAs. Intriguingly, MAFG loss prevents insulinevoked activation of mTORC1 signaling, presumably interfering with protein translation in hepatocytes. We further observe that obesity-repressed LincIRS2 is negatively controlled by MAFG and CRISPR–Cas9-mediated knockout, or antisensemediated RNA interference of LincIRS2 causes hyperglycemia, insulin resistance, likely caused by alterations in glucogenic gene expression in lean mice

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