Background: High-energy diets enriched in simple sugars and saturated fatty acids alter metabolic homeostasis, yet how distinct nutrients are integrated at the transcriptional level remains incompletely understood. Methods: Here, we profiled the larval midgut transcriptome of Drosophila melanogaster following 24 h exposure to diets enriched with 5% fructose (FD), 1% palmitic acid (PD), or their combination (MD). RNA sequencing (Illumina NovaSeq) was performed on pooled third-instar larval midguts, and differential expression analyses were conducted to identify diet-associated transcriptional changes. Results: The results revealed extensive transcriptional remodeling, with most responses being diet-specific, alongside a conserved core of genes regulated across all treatments. Shared transcriptional signatures were associated with proteostasis and amino acid transport pathways. Comparative and pattern-based analyses further uncovered discordant gene sets and pathway enrichments that were unique to individual diets or to the combined exposure. Notably, the mixed diet induced distinct expression patterns with specific functional signatures that were not predictable from either nutrient alone. Conclusions: Together, these findings indicate that the larval midgut integrates carbohydrate and lipid inputs through coordinated and context-dependent transcriptional responses, highlighting the importance of nutrient combinations in shaping epithelial metabolic programs.
Castañeda-Partida et al. (Sat,) studied this question.