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

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

doi:10.1038/s41467-020-14323-y

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

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 DieterichHildegard 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

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	644
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14323-y
Publication status	Published - 2020 Dec 1

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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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., ... Kornfeld, J. W. (2020). A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. Nature communications, 11(1), [644]. https://doi.org/10.1038/s41467-020-14323-y

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: Nature communications, Vol. 11, No. 1, 644, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

Pradas-Juni, M, Hansmeier, NR, Link, JC, Schmidt, E, Larsen, BD, Klemm, P, Meola, N, Topel, H, Loureiro, R, Dhaouadi, I, Kiefer, CA, 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, DFD, Kulkarni, RN, Zevnik, B, Tröder, SE, Knippschild, U, Edwards, PA, Lee, RG, Yamamoto, M, Ulitsky, I, Fernandez-Rebollo, E, Vallim, TQDA & Kornfeld, JW 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

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. / A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. In: Nature communications. 2020 ; Vol. 11, No. 1.

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title = "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.",

author = "Marta Pradas-Juni and Hansmeier, {Nils R.} and Link, {Jenny C.} and Elena Schmidt and Larsen, {Bj{\o}rk Ditlev} and Paul Klemm and Nicola Meola and Hande Topel and Rute Loureiro and Ines Dhaouadi and Kiefer, {Christoph A.} and Robin Schwarzer and Sajjad Khani and Matteo Oliverio and Motoharu Awazawa and Peter Frommolt and Joerg Heeren and Ludger Scheja and Markus Heine and Christoph Dieterich and Hildegard B{\"u}ning and Ling Yang and Haiming Cao and Jesus, {Dario F.De} and Kulkarni, {Rohit N.} and Branko Zevnik and Tr{\"o}der, {Simon E.} and Uwe Knippschild and Edwards, {Peter A.} and Lee, {Richard G.} and Masayuki Yamamoto and Igor Ulitsky and Eduardo Fernandez-Rebollo and Vallim, {Thomas Q.de Aguiar} and Kornfeld, {Jan Wilhelm}",

note = "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{\textquoteright} 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.",

year = "2020",

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doi = "10.1038/s41467-020-14323-y",

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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.

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.

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