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

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

doi:10.1038/s41467-018-05933-8

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.

Highlights

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
To identify mRNAs and long noncoding RNAs (lncRNAs) correlating with BAT function, we exposed lean C57BL/6 mice to thermal stress (4 °C for 24 h) compared to 22 °C housed mice or to chronic high-fat-diet (HFD) compared to micronutrient-matched control diet (CD) feeding
Due to its BAT-selective expression—as for Ucp[1] and Elovl[3] (Fig. 1e–g)—and strong eutherian sequence conservation, we focussed on the intergenic lncRNA H19, which was induced in cold-exposed and decreased in obese BAT (Fig. 1g)

Summary

Introduction

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. 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. To gain molecular insights into these processes, we here performed RNA-Sequencing (RNASeq) in BAT of mice exposed cold or exposed to chronic high-fat diet feeding and observed that monoallelically expressed (imprinted) lncRNA H19 correlated with BAT activation in mouse, and humans. We found that many adipose-selective imprinted genes expressed from paternal alleles were absent from BAT and could demonstrate that H19 forms H19-MBD1 chromatin modifier complexes that repress paternally expressed imprinted genes in brown, not white, adipocytes, thereby serving as selective PEG gatekeeper in BAT

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