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Developmental biology - Genes|
Dangerous Fat Comes From Dad - Good Fat From Mom
H19 belongs to the one percent of our genes, which we inherit exclusively from either our mother or father, our monoallelic genes.
Professors Jan-Wilhelm Kornfeld and Martin Bilban are delighted to have these results as they constitute a first step towards development of better treatments for obesity.
Using mouse models, the team identified how overexpression of H19 controls brown fat cells, protecting against obesity and insulin resistance. They also detected similar patterns of H19 gene control in obese humans. Professor Jan-Wilhelm Kornfeld hopes these results will be the first steps to developing new and improved treatments for obesity-related diseases.
The work is published in the journal Nature Communications.
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.
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 Zentis, Ulf Andersson Ørom, Jörg Heeren, Matthias Blüher, Martin Bilban and Jan-Wilhelm Kornfeld.
Jan-Wilhelm Kornfeld's research is supported by the Danish Diabetes Academy, founded by the Novo Nordisk Foundation.
We thank Christiane Schäfer and Pia Scholl for HE stainings and Beatrix Martiny for electron microscopy and Julia Husa and Markus Jeitler for help with cell culture and RNA-Seq. We acknowledge Jens Alber for technical assistance. Jenny Blommer determined TG and total cholesterole levels. Linheng Li from the Stowers Institute provided H19-DMRflDMR/flDMR mice. We thank Christian Frese, Brigitte Kisters-Woike, and Corinna Klein from CECAD Proteomics Core Facility. J.W.K., E.S., I.G., N.H., S.K., and M.O. are supported by the Emmy-Noether Program of the Deutsche Forschungsgemeinschaft (DFG; KO4728/1.1). J-W.K. receives funding from University of Southern Denmark (SDU) and Danish Diabetes Academy (DDA), which is funded by Novo Nordisk Fonden (NNF). M.P.J is grateful for support by CECAD. R.L., E.F-R., M.P.J., and P.K. receive support from the European Research Council (ERC) Starting Grant TransGenRNA (No. 675014). E.S. is supported by Evangelisches Studienwerk Villigst. S.K appreciates support from DAAD. N.R.H. received a stipend from the Cologne Graduate School for Ageing (CGA). E.N. was supported by an Alexander-von-Humboldt postdoctoral fellowship. This work was supported by the DFG, Obesity Mechanisms (SFB 1052, B01) to M.B.
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A father's contribution to body fat is on the stomach, thighs and backside. While the mother
contributes brown fat and an ongoing metabolic fight against obesity. Photo: public domain.