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Genome-wide analysis of diet and gene interactions in Drosophila uncovers the glucose transporter, CG4607, as a diet-responsive gene

It is clear that both genetic and environmental factors contribute to metabolic health. However, they do not act in isolation. Here, we sought to understand how the interaction between genes and diet influence the ability to store and utilise nutrients, a major determinant of metabolic disease. We achieved this by subjecting the Drosophila Genetic Reference Panel (DGRP), comprising 200 genetically divergent inbred fly strains, to diets varying in sugar, fat and protein content, and assessing starvation resistance, a proxy for an obesogenic phenotype. We discovered heterogeneity in the response to diet, as strains that were starvation resistant on one diet, were starvation sensitive on another. This indicates that genetics plays a major role in governing the diet-health axis. Furthermore, we discovered a diet-dependent heritability in starvation resistance, where high sugar and high protein diets had a greater genetic contribution to the variation in starvation resistance than those that contained fat. To uncover the genetic underpinnings of this variation in starvation response, we mapped 1,350 diet-responsive SNPs in 585 genes, 356 of which have human orthologues. We validated 39 candidate genes using whole-body knockdown and identified a number of novel genes regulating diet-dependent starvation resistance. One such gene was CG4607, a GLUT6/GLUT8 homolog, which was required for glucose tolerance, storage and utilization. A whole-body knock down of CG4607 led to a severe carbohydrate intolerance with the animals dying within 3 days from the start of the feeding. On the other hand, the CG4607 knockdown animals showed starvation sensitivity on a high protein diet. Overall, this study provides definitive evidence that individuals possess optimal dietary environments based on genetic heterogeneity thus offering strong support for nutrigenomic strategies to map such interactions in humans.