RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders

Abstract

The paternal heredity of obesity and diabetes induced by a high-fat and/or high-sugar diet (Western-like diet) has been demonstrated through epidemiological analysis of human cohorts and experimental analysis, but the nature of the hereditary vector inducing this newly acquired phenotype is not yet well defined. Here, we show that microinjection of either testis or sperm RNA of male mice fed a Western-like diet into naive one-cell embryos leads to the establishment of the Western-like diet-induced metabolic phenotype in the resulting progenies, whereas RNAs prepared from healthy controls did not. Among multiple sequence differences between the testis transcriptomes of the sick and healthy fathers, we noted that several microRNAs had increased expression, which was of interest because this class of noncoding RNA is known to be involved in epigenetic control of gene expression. When microinjected into naive one-cell embryos, one of these small RNA, i.e., the microRNA miR19b, induced metabolic alterations that are similar to the diet-induced phenotype. Furthermore, this pathological phenotype was inherited by the offspring after crosses with healthy partners. Our results indicate that acquired food-induced trait inheritance might be enacted by RNA signalling.

tRNA fragments: novel players in intergenerational inheritance

“…In the new paper published in Science, they used hepatic Squalene epoxidase (Sqle) expression in offspring resulting from IVF as a read-out for successful transmission of a phenotype. Consistent with a previous study [5], they report altered miRNA levels in sperm of males subjected to altered diet, but subsequently focused on tRNA fragments [7] which they found to be the most abundant class of RNA in mature sperm and therefore in their opinion have the highest chance to be functionally relevant in the zygote after fertilization.…”

“…To establish a connection between tRF-mediated regulation of gene expression in the embryo and the specifically gained tRFs during sperm transit through the epididymis, they report decreased MERVL target expression in zygotes generated by IVF with cauda sperm as compared to testicular sperm. Sharma et al [7] interpret that solely sperm tRFs gained during spermatogenesis enable full elicitation of expression changes in offspring, while the study from Grandjean et al [5] shows the induction of a full metabolic phenotype after total testis RNA injection. Obvious next steps should involve the investigation of the biological consequences of altered MERVL target expression.…”

“…Recently, Grandjean et al [5] provided insight into the potential of high-fat/high-sugar diet-altered testis and/or sperm RNA and/or single miRNA to recapitulate a metabolic phenotype in the offspring obtained from RNAinjected naïve embryos.…”

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

“…Remarkably, in a subsequent study, these 339 authors reported that inserting only these nine miRNAs into normal zygotes was sufficient to induce 340 the same phenotype indicative of paternal stress (Rodgers et al 2015). Similarly, it has been reported 341 that injection of candidate miRNAs into normal zygotes recapitulates hereditary metabolic syndrome 342 associated with paternal obesity (Grandjean et al 2015). Thus, taken together, the evidence provides a 343 strong case for miRNAs as a principal language of environmental inheritance.…”

Cell-secreted vesicles containing microRNAs as regulators of gamete maturation

“…These are scarce in testicular sperm but acquired as sperm mature in the epididymis after fusion with epididymosomes (Sharma et al 2015). Furthermore, mice fed with western-like diet (high-fat or high-sugar) presented with altered sperm microRNA profiles, and the subsequent transfer of altered microRNAs through ICSI led to the establishment of western-like-dietinduced metabolic phenotype in offspring (Grandjean et al 2015).…”