LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat

Elena Schmidt, Ines Dhaouadi, Isabella Gaziano, Matteo Oliverio, Paul Klemm, Motoharu Awazawa, Gerfried Mitterer, Eduardo Fernandez-Rebollo, Marta Pradas-Juni, Wolfgang Wagner, Philipp Hammerschmidt, Rute Loureiro, Christoph Kiefer, Nils R. Hansmeier, Sajjad Khani, Matteo Bergami, Markus Heine, Evgenia Ntini, Peter Frommolt, Peter ZentisUlf Andersson Ørom, Jörg Heeren, Matthias Blüher, Martin Bilban, Jan Wilhelm Kornfeld*

*Corresponding author for this work

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Abstract

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans.

Original languageEnglish
Article number3622
JournalNature Communications
Volume9
Issue number1
Number of pages16
ISSN2041-1723
DOIs
Publication statusPublished - 6. Sep 2018

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    Schmidt, E., Dhaouadi, I., Gaziano, I., Oliverio, M., Klemm, P., Awazawa, M., Mitterer, G., Fernandez-Rebollo, E., Pradas-Juni, M., Wagner, W., Hammerschmidt, P., Loureiro, R., Kiefer, C., Hansmeier, N. R., Khani, S., Bergami, M., Heine, M., Ntini, E., Frommolt, P., ... Kornfeld, J. W. (2018). LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat. Nature Communications, 9(1), [3622]. https://doi.org/10.1038/s41467-018-05933-8