Drosophila as a model to study the genetic mechanisms of parental high-fat diet and its effects on the trans-generational initiation of obesity and heart dysfunction. Ryan Tyge Birse, Hannah Catan, Kathryn Reardon, Sean Oldham, Rolf Bodmer. Program of Development and Aging, Sanford-Burnham Medical Research Institute, La Jolla, CA.

   Given the early onset of the obesity epidemic, it is plausible that the metabolic state of the pregnant mother may contribute to the susceptibility of the offspring to obesity. Studies have shown that the diet of the pregnant mother correlates with disease type and its postnatal appearance. These studies led to a theory of maternal influences on disease causation, which states that the uterine nutritional environment is a critical determinant for disease development in the offspring. Although maternal effects in these cases have been shown, the genetic and mechanistic basis has yet to be elucidated. Therefore, it would be beneficial to study the central aspects of obesity in parallel with the control of heart function, in a simplified system. We have recently established the Drosophila as a tool for discovering not only the conserved genetic mechanisms that maintain heart function but also the genetic mechanisms of metabolism, as it relates to heart function. We find that there is a persistent transgenerational effect on lipid metabolism and heart function in offspring from parents on a high fat diet (HFD). We also found that a HFD induces a metabolic shift to glycolysis and lipogenesis. We also show that tissues specific overexpression (OE) of Bmm lipase can protect the progeny from the adverse effects of a maternal HFD. To further investigate Bmm activity I have expressed Bmm in the embryonic, larval and adult fatbody (FB) which induced a postnatal protection for the progeny from parents on a HFD. Finally I investigated the affects of sirtuin (Sir2) OE in the FB and heart since it is an epigenetic regulator known to be involved in metabolism. From these studies I found strikingly similar phenotypes to those of the Bmm OE and we have also found that Sir2 OE caused an increase in Bmm transcript levels. Therefore this study elucidates a potential epigenetic mechanism working through Sir2 and Bmm that regulates the effects from a maternal diet on its progeny.