Early life high-fat diet exposure modulates adult metabolic phenotypes in Drosophila

Early-life exposure to dietary excess of lipids increases lifelong vulnerability to metabolic dysfunction, but the determinants of this susceptibility remain unclear. Here, we combine paired-tissue transcriptomics (whole head and fat body), metabolomics, and gut microbiota profiling in Drosophila melanogaster to define how transient developmental exposure to a high-fat diet (HFD) remodels adult metabolism. Larval HFD exposure was associated with extensive transcriptional remodeling in the adult fat body, including coordinated repression of tricarboxylic acid (TCA) cycle and oxidative phosphorylation genes, accompanied by increased ROS accumulation and reduced mitochondrial bioenergetic function. In contrast, the whole-head transcriptome showed a weaker response to HFD than the fat body. Integrated host-microbiome profiling revealed persistent remodeling of the gut microbial community, with altered bacterial diversity and structure. Targeted adult interventions with the NAD⁺ precursor nicotinamide riboside, the TCA intermediate α-ketoglutarate, or commensal bacteria (Acetobacter and Lactobacillus spp.) restored mitochondrial redox balance, improved respiratory capacity, and extended lifespan. Together, these findings identify mitochondrial dysfunction and microbial remodeling as enduring features of developmental dietary lipid stress and suggest that this metabolic state remains partially reversible through mitochondrial and microbiota-directed interventions.