A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism
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A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. / Pradas-Juni, Marta; Hansmeier, Nils R; Link, Jenny C; Schmidt, Elena; Larsen, Bjørk Ditlev; Klemm, Paul; Meola, Nicola; Topel, Hande; Loureiro, Rute; Dhaouadi, Ines; Kiefer, Christoph A; Schwarzer, Robin; Khani, Sajjad; Oliverio, Matteo; Awazawa, Motoharu; Frommolt, Peter; Heeren, Joerg; Scheja, Ludger; Heine, Markus; Dieterich, Christoph; Büning, Hildegard; Yang, Ling; Cao, Haiming; Jesus, Dario F De; Kulkarni, Rohit N; Zevnik, Branko; Tröder, Simon E; Knippschild, Uwe; Edwards, Peter A; Lee, Richard G; Yamamoto, Masayuki; Ulitsky, Igor; Fernandez-Rebollo, Eduardo; Vallim, Thomas Q de Aguiar; Kornfeld, Jan-Wilhelm.
In: NAT COMMUN, Vol. 11, No. 1, 31.01.2020, p. 644.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism
AU - Pradas-Juni, Marta
AU - Hansmeier, Nils R
AU - Link, Jenny C
AU - Schmidt, Elena
AU - Larsen, Bjørk Ditlev
AU - Klemm, Paul
AU - Meola, Nicola
AU - Topel, Hande
AU - Loureiro, Rute
AU - Dhaouadi, Ines
AU - Kiefer, Christoph A
AU - Schwarzer, Robin
AU - Khani, Sajjad
AU - Oliverio, Matteo
AU - Awazawa, Motoharu
AU - Frommolt, Peter
AU - Heeren, Joerg
AU - Scheja, Ludger
AU - Heine, Markus
AU - Dieterich, Christoph
AU - Büning, Hildegard
AU - Yang, Ling
AU - Cao, Haiming
AU - Jesus, Dario F De
AU - Kulkarni, Rohit N
AU - Zevnik, Branko
AU - Tröder, Simon E
AU - Knippschild, Uwe
AU - Edwards, Peter A
AU - Lee, Richard G
AU - Yamamoto, Masayuki
AU - Ulitsky, Igor
AU - Fernandez-Rebollo, Eduardo
AU - Vallim, Thomas Q de Aguiar
AU - Kornfeld, Jan-Wilhelm
PY - 2020/1/31
Y1 - 2020/1/31
N2 - 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.
AB - 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.
KW - Aged
KW - Animals
KW - Diabetes Mellitus, Type 2/genetics
KW - Glucose/metabolism
KW - Humans
KW - Liver/metabolism
KW - MafG Transcription Factor/genetics
KW - Male
KW - Mice
KW - Middle Aged
KW - Obesity/genetics
KW - RNA, Long Noncoding/genetics
KW - RNA, Messenger/genetics
KW - Repressor Proteins/genetics
KW - TOR Serine-Threonine Kinases/genetics
U2 - 10.1038/s41467-020-14323-y
DO - 10.1038/s41467-020-14323-y
M3 - SCORING: Journal article
C2 - 32005828
VL - 11
SP - 644
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -