Grand paternal inheritance of an acquired metabolic trait induced by ancestral obesity is associated with sperm RNA

Parental exposure to an environmental challenge can induce phenotypes in offspring independent of the inherited DNA sequence. Whether such acquired traits can be inherited, i.e., can manifest in a generation beyond that exposed to the precipitating insult as germ cells, is unclear. Here we report a latent metabolic phenotype induced by paternal obesity that is inherited into a second generation, without germ cell exposure. Sons of obese male mice exhibit defects in glucose and lipid metabolism that are only unmasked by post-weaning dietary challenge, yet they transmit these defects to their own progeny (F2) in the absence of the challenge. F1 sperm exhibit changes in the abundance of several small RNA species, including diet responsive tRNA-derived fragments. These data suggest that induced metabolic phenotypes may be propagated for multiple generations through the actions of noncoding RNA.