The Role of Epigenetics in the Behaviour of Drosophila melanogaster

Type 2 Diabetes (T2D) and obesity are major health concerns of the modern world affecting approximately 8% and 11% of the global population, respectively, making it a clear medical and economic burden. T2D is a systemic dysfunction characterized by the body’s inability to respond to insulin secretion, which is key in maintaining metabolic homeostasis and preventing conditions such as hyperglycemia and glucose intolerance, both of which can lead to serious medical consequences, if left untreated. Onset of T2D is determined by an interplay of many genetic and environmental factors. One of the major risk factors for T2D is obesity, which is having a body mass index (BMI) of 30kg/m2 or higher. Additionally, heritability estimates of T2D and obesity can be as high as 69% and 75%, respectively, and many obesity-associated genetic loci appear in T2D GWAS studies. The occurrence of T2D and obesity are on the rise and the identification of novel genetic risk factors and biological mechanisms underlying metabolic dysfunction has proven to be an essential bottleneck in understanding the complex etiology of these diseases and designing novel therapies.

    In this project, we propose the use of the fruit fly Drosophila melanogaster as a tractable genetic model organism to identify novel genetic factors contributing to insulin signaling regulation and metabolic dysfunction, as in T2D and obesity. In the past several years, Drosophila have been increasingly used to address questions about metabolic function and have successfully identified novel genetic contributors to metabolic disease. Drosophila are a fantastic model for these questions not only because they provide fast, efficient, and economically feasible in vivo assays to address biological questions, but also due to the extensive genetic and anatomical homology between flies and mammals. Approximately 75% of human disease genes have homologs in the Drosophila genome, including insulin/insulin-like growth factor (IGF) and their respective receptor and signaling cascades which exemplify the extensive conservation between flies and mammals. In Drosophila, a Drosophila insulin-like Receptor (dInR) and seven ligands exist, the Drosophila insulin-like peptides (dilps1-7). Dlps 2, 3 and 5 are produced in the Drosophila Insulin-Producing Cells (IPCs), neurosecretory cells exhibiting remarkable developmental, transcriptional and functional similarity to the beta cells of the mammalian pancreas. Disrupting insulin signaling in these cells either by genetic perturbation of key regulators or by ablation of the IPCs themselves produces a robust diabetic phenotype, marked by smaller, hyperglycemic flies. Evidence from our lab and others suggest that regulatory networks regulating IPC development and dilp transcription are conserved, such as Eyeless (mammalian Pax6) and Dachshund (mammalian Dachshund). Additional preliminary data from our lab has identified requirements for novel transcription factors and hormone receptors, most of which have homologs expressed in or required by the mammalian beta cells or developing pancreas. This suggests a remarkable level of conservation of insulin signaling mechanisms between fly and man, and provides a unique opportunity to use these cells as a model to identify novel regulators.

    A complex integration of signals is required in order to attain metabolic homeostasis. Insulin signaling can be regulated by non-autonomous factors deriving from other organs within the anatomy. In mammals, endocrine signals from the liver, brain, and hormone-producing glands such as the gonads are involved in the regulation of beta cell mass or function. For example in Drosophila, it is known that the leptin-like molecule Upd2 signals from the adipose-storing fat body to the IPCs of larvae, a fat body-derived signal in adults has yet to be identified. Additionally, steroid hormones have been implicated in the regulation of insulin signaling, but their precise mechanism and directionality of this regulation remain ambiguous. Availability of genetic tools and high-power analyses are facilitating the construction of a more complete picture of regulation, providing an opportunity to study more complex questions about endocrine regulatory networks unaddressable in other systems.

Given the power of Drosophila as a genetic model and the recent technological advances, we propose that Drosophila can be used to identify novel genetic regulators of insulin signaling and lipid storage, further advancing fundamental knowledge that can provide insights into the systemic dysregulation underlying diseases such as T2D and obesity.