A multi-component screen for feeding behaviour and nutritional status in Drosophila to interrogate mammalian appetite-related genes

Objective: More than 300 genetic variants have been robustly associated with measures of human adiposity. Highly penetrant mutations causing human obesity do so largely by disrupting satiety pathways in the brain and increasing food intake. Most of the common obesity-predisposing variants are in, or near, genes that are expressed highly in the brain, but little is known about their function. Exploring the biology of these genes at scale in mammalian systems is challenging. We sought to establish and validate the use of a multicomponent screen for feeding behaviour phenotypes taking advantage of the tractable model organism Drosophila melanogaster. Methods: We validated a screen for feeding behaviour in Drosophila by comparing results after disrupting expression of centrally-expressed genes that influence energy balance in flies to those of ten control genes. We then used this screen to explore the effects of disrupted expression of genes that are either a) implicated in energy homeostasis through human genome wide association studies (GWAS) or b) expressed and nutritionally responsive in specific populations of hypothalamic neurons with a known role in feeding/fasting. Results: Using data from the validation study to classify responses, we studied 53 Drosophila orthologues of genes implicated by human GWAS in body mass index (BMI) and found that 15 significantly influenced feeding behaviour or energy homeostasis in the Drosophila screen. We then studied 50 Drosophila homologues of 47 murine genes that are reciprocally nutritionally regulated in POMC and AgRP neurons. Seven of these 50 genes were found by our screen to influence feeding behaviour in flies. Conclusion: Here, we demonstrate the utility of Drosophila as a tractable model organism in a high-throughput genetic screen for food intake phenotypes. This simple and cost-efficient strategy is ideal for high-throughput interrogation of genes implicated in feeding behaviour and obesity in mammals, and will facilitate the process of reaching a functional understanding of obesity pathogenesis.