Transgenerational inheritance of paternal metabolic programming linked to small noncoding RNA

Transgenerational inheritance of an environmentally-induced trait requires that the induced phenotype manifest in generations beyond those that were exposed as germ cells. Here we demonstrate that paternal obesity in mice confers a latent metabolic phenotype not only in F1 sons, but also in F2 grandsons who were never exposed to obesity. F1 and F2 male progeny of obese sires exhibit nearly identical metabolic phenotypes that can be explained in part by stable alterations in hepatic miR-122, a key regulator of fatty-acid metabolism. Both the physiological and molecular alterations induced by paternal obesity are inherited into F2 entirely through the male line, but become attenuated by F3. Our findings demonstrate true transgenerational inheritance of an acquired trait in mammals. The association between the acquired phenotype and levels of several abundant small noncoding RNAs in spermatozoa implicates small RNAs in the mechanism of inheritance.