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Proc Natl Acad Sci U S A. 2019 May 21;116(21):10547-10556. doi: 10.1073/pnas.1820810116. Epub 2019 May 6.

Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs.

Author information

1
Laboratory of Translational Nutrition Biology, Department of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland.
2
Institute of Anthropology, Johannes Gutenberg University Mainz, 55099 Mainz, Germany.
3
Center for Transgenic Models, University of Basel, 3350 Basel, Switzerland.
4
Functional Genomics Center Zurich, ETH Zurich, 8057 Zurich, Switzerland.
5
Laboratory of Translational Nutrition Biology, Department of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland; daria-peleg@ethz.ch.

Abstract

There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as CHRNA2 and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.

KEYWORDS:

epigenetic; maternal; obesity; overnutrition; sperm RNA

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