Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice

Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, consequences multigenerational feeding on progeny remain largely unknown. Here, we show maintaining Western for five consecutive generations in mice induces enhancement fat mass and related diseases over generations. Strikingly, chow-diet-fed progenies from these Western-diet-fed males develop ‘healthy’ overweight phenotype characterized normal glucose metabolism without fatty liver persists four subsequent Mechanistically, sperm RNA microinjection experiments into zygotes suggest RNAs are sufficient establishment but not long-term maintenance epigenetic inheritance pathologies. Progressive permanent deregulation successive may contribute to worldwide epidemic diseases.