Sick, not thick: Are high-fat diets the right context for the obesity disease model?

Numerous studies use a high-fat diet (HFD), typically enriched with 10-30% dietary fat, to model obesity in Drosophila melanogaster. A greater number of peer-reviewed publications puts the HFD study in the context of obesity when reporting about neurodegeneration, oxidative stress, or other biological effects of this diet.
HFD, a powerful nutritional tool, indeed demonstrates a long list of negative health consequences, including shortened lifespan, shifted intestinal microbiota, impaired fertility and climbing ability. However, is this enough to conclude that HFD is suitable to model the obesity?
We have analyzed various biomarkers of D. melanogaster, strain ORC, fed with 10% or 20% butter fat, lard or coconut oil, to investigate whether we can observe some typical characteristics of human obesity and reproduce some of the reported negative health effects connected to HFD in the context of obesity. We have run a multiplexing bead-based mRNA analysis of the selected genes that may be impacted by the excessive fat. Specifically, we had quantified gene expression of adipokinetic hormone Akh, insulin-like peptides ilp2, ilp3,
ilp5, insulin and ecdysone receptor (InR and EcR), as well as metabolic enzymes lactate dehydrogenase Ldh, phosphoglucomutase 1 Pgm1, methyltransferase 2 Mt2, methionine sulfoxide reductase A MrsA and lipid homeostasis-related genes Orp8, SelR, and CREG. Additionally, we have cultivated 200 fruit flies individually and weighed every fly before and after one week of the HFD treatment.
While obesity is most often characterized by an increase in weight via excessive fat, we have observed no significant weight change in the male flies and even a weight decrease in the females. We also failed to reproduce the previously reported ROS elevation in the HFD-fed fruit flies. On the contrary, we observed no changes in whole-body reactive species after 1-week HFD-treatment of males and females. Moreover, sexual dimorphism of the Drosophila metabolism was observed in the gene expression. In females, Akh, CREG, EcR, ilp2, InR, Ldh, Pgm1, Orp8, SelR were significantly upregulated in the group with 20% coconut oil but not animal fats. In males, only Orp8 was significantly altered by the HFD, leading us to believe that HFD makes flies sick and physically inactive due to the sex-specific metabolic disturbances, other than dramatic weight gain.
We conclude that HFD may be a valuable nutritional tool to simulate different pathological conditions in the fruit fly, but it should be used with caution in the context of obesity modelling.