View Program - 63rd Annual Drosophila Research Conference

All growth during the Drosophila life cycle is restricted to larval development, when animals increase their body size ~200-fold over the course of four days. In order to support this exponential growth rate, larvae up-regulate glycolytic metabolism as a means to generate the necessary energy and biomass. The resulting metabolic program exhibits the hallmark characteristics of the Warburg effect, or aerobic glycolysis, which is also used by many types of cancer cells to fuel tumor growth. Thus, our ability to study the mechanism that controls larval glycolytic metabolism provides a powerful genetic model to explore how aerobic glycolysis is regulated in vivo. In this regard, the fly provides an unusual opportunity to identify the endogenous mechanisms that turn off aerobic glycolysis in vivo - unlike tumors, where the Warburg effect is indefinitely activated, fly larvae down-regulate glycolysis at the end of the growth phase in a predictable manner. Using a candidate gene approach, we are exploring two mechanisms that potentially control the global down-regulation of glycolytic gene expression at the onset of metamorphosis. First, we are exploring the possibility that the late-larval pulse of 20-hydroxyecdysone (20E) is necessary to downregulate glycolytic gene expression. Our preliminary studies support this hypothesis, as two metabolite markers of aerobic glycolysis, lactate and 2-hydroxyglutarate, fail to be downregulated in larvae lacking 20E signaling. In addition, we are examining the role of the Drosophila Estrogen Related Receptor (dERR) in this late-larval metabolic transition. Since dERR is required to activate glycolytic gene expression at the onset of larval development, and previous studies demonstrate that dERR activity is down-regulated during the late-L3 stage, we are testing the hypothesis that ectopic dERR activation would prevent down-regulation of glycolytic gene expression. Here too, our preliminary data indicate that ERR signaling may need to be attenuated to allow for the downregulation of glycolysis prior to metamorphosis. Overall, our findings suggest that nuclear receptor signaling plays a key role in the transcriptional down-regulation of glycolytic genes at the cessation of larval growth.

Investigating the mechanisms that control glycolytic gene expression at the cessation of larval growth