The obesity epidemic, recognized in developed nations for decades, is now a worldwide phenomenon. All age groups are affected, including women of childbearing age, fueling concern that maternal obesity before and during pregnancy and lactation impairs developmental establishment of body weight regulatory mechanisms in the fetus or infant, causing transgenerational amplification of obesity prevalence and severity. The biological mechanisms underlying such processes remain unknown. We used agouti viable yellow (Avy) mice to test the hypothesis that maternal obesity induces transgenerational amplification of obesity. We passed the Avy allele through three generations of Avy/a females and assessed cumulative effects on coat color and body weight. By studying two separate but contemporaneous populations of mice, one provided a standard diet and the other a methyl-supplemented diet that induces DNA hypermethylation during development, we tested whether potential transgenerational effects on body weight might be mediated by alterations in epigenetic mechanisms including DNA methylation. The genetic tendency for obesity in Avy mice was progressively exacerbated when the Avy allele was passed through successive generations of obese Avy females. This transgenerational amplification of body weight was prevented by a promethylation dietary supplement. Importantly, the effect of methyl supplementation on body weight was independent of epigenetic changes at the Avy locus, indicating this model may have direct relevance to human transgenerational obesity. Our results show that in a population with a genetic tendency for obesity, effects of maternal obesity accumulate over successive generations to shift the population distribution toward increased adult body weight, and suggest that epigenetic mechanisms are involved in this process.

Methyl donor supplementation prevents transgenerational amplification of obesity