Metabolic regulation at the intersection of genes and environment

The incidence of complex metabolic disease has risen to an alarming level in the last several decades. This elevated frequency has been accompanied by increased social and financial costs, with nearly $250 billion spent each year on diabetes alone. Despite this growing health crisis, only a small percentage of the heritable risk for these disorders has been identified. Possible sources of this missing heritability include geneenvironment interactions and gene-gene interactions, as well as the influence of parental or grandparental metabolism. In this work, I have focused on characterizing potential sources of these effects and the impacts they may have on physiology. The deacetylase Sir2 is a conserved metabolic regulator whose influence in normal and pathological physiology has been well documented but little understood. In characterizing Drosophila sir2 mutants, I discovered that loss of sir2 leads to progressive defects in carbohydrate and lipid homeostasis as well as the development of insulin resistance and glucose intolerance. I found that these functions of Sir2 are localized to the fat body and partially restore metabolic function by overexpressing the nuclear receptor dHNF4. Finally, I found that dHNF4 acetylation and stability is altered in sir2 mutants, suggesting that this factor is a key and direct target for Sir2 in the maintenance of metabolic flexibility. In the second part of this work, I focus on the development of both dietary and genetic paradigms to induce metabolic dysfunction in the parental generation that can iv lead to heritable physiological defects in their progeny. I found that either method of altering parental metabolic state can induce heritable changes in offspring metabolism under both basal and challenge conditions for at least two generations. I also identified key sources of genetic and environmental variation that influence the degree of parental dysfunction as well as the degree of physiological responses in the progeny. These studies lay the groundwork for more careful characterization of progeny responses, the molecular pathways affected in these progeny, as well as the mechanisms by which these changes are inherited.