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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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.).
The authors declare no competing interests.
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Sun, W., Dong, H., Becker, A.S. et al. Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring. Nat Med 24, 1372–1383 (2018). https://doi.org/10.1038/s41591-018-0102-y
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