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

Abstract

There is a growing body of evidence linking maternal overnutri-tion to obesity and psychopathology that can be conserved acrossmultiple generations. Recently, we demonstrated in a maternalhigh-fat diet (HFD; MHFD) mouse model that MHFD inducedenhanced hedonic behaviors and obesogenic phenotypes thatwere conserved across three generations via the paternal lineage,which was independent of sperm methylome changes. Here, weshow that sperm tRNA-derived small RNAs (tsRNAs) partly contrib-ute to the transmission of such phenotypes. We observe increasedexpression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFDmale into normal zygotes reproduces obesogenic phenotypes andaddictive-like behaviors, such as increased preference of palatablefoods and enhanced sensitivity to drugs of abuse in the resultantoffspring. The expression of several of the differentially expressedsperm tsRNAs predicted targets such asCHRNA2and GRIN3A, whichhave been implicated in addiction pathology, are altered in themesolimbic reward brain regions of the F1-HFD father and the re-sultant HFD-tsRNA offspring. Together, our findings demonstratethat sperm tsRNA is a potential vector that contributes to the trans-mission of MHFD-induced addictive-like behaviors and obesogenicphenotypes across generations, thereby emphasizing its role in di-verse pathological outcomes.