Abstract

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

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Acknowledgements

We are grateful to M. Stoffel, J. Krützfeldt and members of the Wolfrum lab for helpful discussions, K. Tabbada for assistance with WGBS high-throughput sequencing, and F. Krueger and S. Andrews for help with bioinformatics analysis. We thank K. De Bock and F. Zheng for the IB4 antibody and K. A. Rollins for editing the manuscript. Data produced and analyzed in this paper were generated in collaboration with the Genetic Diversity Center (GDC) and Functional Genomics Center Zurich (FGCZ). The work was supported by the Swiss National Science Foundation (SNSF; C.W. and F.v.M.).

Author information

Author notes

  1. These authors contributed equally: Wenfei Sun and Hua Dong.

Affiliations

  1. Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland

    • Wenfei Sun
    • , Hua Dong
    • , Anton S. Becker
    • , Dianne H. Dapito
    • , Salvatore Modica
    • , Gerald Grandl
    • , Lennart Opitz
    • , Vissarion Efthymiou
    • , Leon G. Straub
    • , Gitalee Sarker
    • , Miroslav Balaz
    • , Lucia Balazova
    • , Aliki Perdikari
    • , Elke Kiehlmann
    • , Daria Peleg-Raibstein
    •  & Christian Wolfrum
  2. Institute of Diagnostic and Interventional Radiology, University Hospital of Zurich, Zurich, Switzerland

    • Anton S. Becker
  3. Clinic of Nuclear Medicine, University Hospital of Zurich, Zurich, Switzerland

    • Anton S. Becker
    • , Sara Bacanovic
    • , Caroline Zellweger
    •  & Irene A. Burger
  4. Functional Genomics Center Zurich, ETH Zurich–University of Zurich, Zurich, Switzerland

    • Lennart Opitz
  5. Center for Transgenic Models, University of Basel, Basel, Switzerland

    • Pawel Pelczar
  6. Epigenetics Program, Babraham Institute, Cambridge, UK

    • Wolf Reik
    •  & Ferdinand von Meyenn
  7. Wellcome Trust Sanger Institute, Hinxton, UK

    • Wolf Reik
  8. Department of Medical and Molecular Genetics, King’s College London, London, UK

    • Ferdinand von Meyenn

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Contributions

W.S. and C.W. designed the study; W.S. and H.D. performed all of the experimental work, except that described below; P.P. performed the IVF; S.M. helped with the Seahorse experiments; D.H.D. characterized the Ucp1-DTR-GFP mice; C.W., V.E., M.B. and D.H.D. contributed to the tracing of radiolabeled glucose; E.K. did paraffin sectioning; G.G. quantified lipid droplet sizes; A.P. helped with FACS; V.E. performed automated image analysis; L.G.S. helped with indirect calorimetry analysis; G.S. helped in the analysis of maternal behavior; D.P.-R. and W.S. did the microdialysis studies; A.S.B., I.A.B., S.B. and C.Z. performed the retrospective analysis of BAT in humans; L.O. contributed to RNA-seq data analysis; F.v.M. and W.R. did DNA methylation sequencing and bioinformatic analysis; W.S. and C.W. wrote the manuscript; and F.v.M., A.S.B., I.A.B., D.H.D., S.M., M.B. and L.B. helped with the editing of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Christian Wolfrum.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Tables 3 and 4

  2. Reporting Summary

  3. Supplementary Table 1

    Differentially expressed gene lists of iBAT RNA sequencing

  4. Supplementary Table 2

    Differentially methylated gene lists of sperm whole genome bisulfite sequencing

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DOI

https://doi.org/10.1038/s41591-018-0102-y