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A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism
- Source :
- Pradas-Juni, M, Hansmeier, N R, Link, J C, Schmidt, E, Larsen, B D, Klemm, P, Meola, N, Topel, H, Loureiro, R, Dhaouadi, I, Kiefer, C A, Schwarzer, R, Khani, S, Oliverio, M, Awazawa, M, Frommolt, P, Heeren, J, Scheja, L, Heine, M, Dieterich, C, Büning, H, Yang, L, Cao, H, Jesus, D F D, Kulkarni, R N, Zevnik, B, Tröder, S E, Knippschild, U, Edwards, P A, Lee, R G, Yamamoto, M, Ulitsky, I, Fernandez-Rebollo, E, Vallim, T Q D A & Kornfeld, J-W 2020, ' A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism ', Nature Communications, vol. 11, no. 1, 644 . https://doi.org/10.1038/s41467-020-14323-y, Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.<br />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 :
- MafG Transcription Factor
Male
CRISPR-Cas9 genome editing
0301 basic medicine
Science
General Physics and Astronomy
Biology
Carbohydrate metabolism
Article
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Diabetes mellitus
Gene expression
medicine
Animals
Humans
Gene silencing
Obesity
RNA, Messenger
lcsh:Science
Transcriptomics
PI3K/AKT/mTOR pathway
Aged
2. Zero hunger
Multidisciplinary
TOR Serine-Threonine Kinases
General Chemistry
Metabolism
Middle Aged
medicine.disease
Cell biology
Repressor Proteins
Glucose
030104 developmental biology
Diabetes Mellitus, Type 2
Liver
Cistrome
030220 oncology & carcinogenesis
Long non-coding RNAs
lcsh:Q
RNA, Long Noncoding
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....bd0eb3ef806b4da07fa5eeb76a90ddf4