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
N1 - Funding Information:
We thank Brigitte Hampel and Pia Scholl for H/E stainings, Jens Alber for technical support with indirect calorimetry measurements and mouse handling, and Lisa Czaja for help with RNA-Seq. MPJ was supported by an Albert Renold Travel Fellowship from the European Association for the Study of Diabetes (EASD). H.T. was awarded with a Short-Term Fellowship from the European Molecular Biology Organization (EMBO). J.W.K., M.O. and E.S. were supported by the Emmy-Noether Program of the Deutsche For-schungsgemeinschaft (DFG, KO4728/1.1). J.W.K., B.D.L. and C.K. received funding from the University of Southern Denmark (SDU) and Danish Diabetes Academy (DDA), which is funded by the Novo Nordisk Foundation (NNF). J.W.K., R.L., E.F.R., M.P.J. and P.K. received support from European Research Council Starting (Grant No. 675014). E.S. was supported by Evangelisches Studienwerk Villigst e.V. S.K. appreciates a PhD stipend from the German Academic Exchange Service (DAAD). N.R.H. was awarded with a PhD stipend from the Cologne Graduate School for Ageing (CGA). R.N.K. and D.F.D. received support from NIH Grants RO1 DK103215, RO1 DK67536, RO1 117639, and DK P036836. J.C.L. is supported by UPLIFT: UCLA Postdocs’ Longitudinal Investment in Faculty (Award # K12 GM106996). L.Y. and H.C. were supported by intramural NIH research funding grants (references 1ZIAHL006103 and 1ZIAHL006159). L.Y. was supported by NIH grant K22HL139921. T.Q. de A.V. is funded by NIH grants DK112119 and HL122677 and P.A.E. and T.Q. de A.V. are funded by DK118064.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85078851219&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078851219&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14323-y
DO - 10.1038/s41467-020-14323-y
M3 - Article
C2 - 32005828
AN - SCOPUS:85078851219
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 644
ER -
