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

Significance

Obesity is a major public health issue worldwide. Easy accessibility of junk food is considered a major contributor to the current obesity epidemic. Thus, the impact of maternal overnutrition in determining disease susceptibility in offspring has received wide attention. It has also been shown that the effects of maternal overnutrition are not limited to the immediate offspring but can also be transmitted to successive generations. Among different epigenetic marks, sperm small noncoding RNAs (sncRNAs) have recently been reported as a direct mediator of acquired traits to the progeny following postnatal trauma or paternal diet. Here, we investigate whether sperm sncRNAs contributes to the transmission of metabolic and hedonic phenotypes across generations following maternal overnutrition.

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.