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

^*Kontaktforfatter

Institut for Biokemi og Molekylær Biologi

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstrakt

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.

Originalsprog	Engelsk
Artikelnummer	644
Tidsskrift	Nature Communications
Vol/bind	11
Udgave nummer	1
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-020-14323-y
Status	Udgivet - 2020

Dokumenter og links

10.1038/s41467-020-14323-yLicens: CC BY

Open Access VersionForlagets udgivne version, 2,06 MBLicens: CC BY

Citationsformater

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

@article{8f4015351f85412ca33e8935eebf2715,

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 Jan-Wilhelm Kornfeld",

year = "2020",

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

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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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, J-W 2020, 'A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism', Nature Communications, bind 11, nr. 1, 644. https://doi.org/10.1038/s41467-020-14323-y

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

Y1 - 2020

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.

U2 - 10.1038/s41467-020-14323-y

DO - 10.1038/s41467-020-14323-y

M3 - Journal article

C2 - 32005828

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 644

ER -

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

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