Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity

• Paternal obesity induces latent defects in metabolism in F1 sons.
• Metabolic disease in F1 sons is exposed by short challenge with a Western diet.
• F1 sons transmit their phenotype to F2 grandsons in the absence of dietary challenge.
• F1 sperm exhibit changes to prominent small RNA species.

ObjectiveParental obesity can induce metabolic phenotypes in offspring independent of the inherited DNA sequence. Here we asked whether such non-genetic acquired metabolic traits can be passed on to a second generation that has never been exposed to obesity, even as germ cells.MethodsWe examined the F1, F2, and F3 a/a offspring derived from F0 matings of obese prediabetic Avy/a sires and lean a/a dams. After F0, only lean a/a mice were used for breeding.ResultsWe found that F1 sons of obese founder males exhibited defects in glucose and lipid metabolism, but only upon a post-weaning dietary challenge. F1 males transmitted these defects to their own male progeny (F2) in the absence of the dietary challenge, but the phenotype was largely attenuated by F3. The sperm of F1 males exhibited changes in the abundance of several small RNA species, including the recently reported diet-responsive tRNA-derived fragments.ConclusionsThese data indicate that induced metabolic phenotypes may be propagated for a generation beyond any direct exposure to an inducing factor. This non-genetic inheritance likely occurs via the actions of sperm noncoding RNA.