3. The transgenerational inheritance of metabolic state

Central to the epidemic of metabolic disorders is a striking correlation between the metabolic health of parents and that of their offspring. There is a vast literature describing this phenomenon in rats and mice, demonstrating that temporary nutritional changes in the parental generation can have major effects on the metabolic status of their adult offspring maintained on a normal diet. This includes an increased risk for developing type 2 diabetes and obesity. Epidemiological studies of adults born during the Dutch Hunger Winter of 1944, along with other more correlative studies, have demonstrated that similar inherited effects on metabolism can be seen in humans. Molecular studies have shown that changes in epigenetic chromatin marks in offspring are associated with changes in parental diet, providing a potential molecular mechanism to explain the inherited effects on metabolism. In spite of these extensive studies, however, the research in this area remains correlative. Only a few genetic approaches have been used to characterize the inheritance of metabolic state, and there is no defined molecular mechanism to explain this association. We have discovered that the fruit fly Drosophila shares the ability to link the metabolic status of parents with that of their offspring, that transmission can be seen through both the male and female germline, that metabolic dysfunction carries through to the F2 and F3 generations, and that the phenotypes are similar to those reported in rodent and human studies. We have identified a nuclear receptor that contributes to this response, DHR96, and have shown that genetic changes in epigenetic state can lead to metabolic dysfunction in the offspring. Our goal in this research is to exploit the genetic strengths of Drosophila for studies of metabolic regulation and epigenetic control, providing, for the first time, a simple genetic system to define the molecular mechanisms that control transgenerational metabolic inheritance.