(324f) Identification of High Sugar Diet-Induced Dysregulated Metabolic Pathways in Muscle Using Tissue-Specific Metabolic Models in Drosophila

Individual tissues perform highly specialized metabolic functions to maintain whole-body homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, a lack of tissue-specific metabolic models makes it challenging to quantitatively assess the metabolic processes of individual tissues and disease models in this organism. To address this issue, we reconstructed 32 tissue-specific genome-scale metabolic models (GEMs) using pseudo-bulk single cell transcriptomics data, revealing distinct metabolic architectures in different tissues. Specifically, by integrating kinetics, proteomics, and flux analyses, we predicted tissue-dependent metabolic pathway activities, recapitulating known tissue functions and revealing tissue-specific metabolic signatures, as supported by metabolite profiling analyses. To demonstrate the utility of the tissue-specific GEMs in a disease model setting, we evaluated the effect of a high sugar diet (HSD) on muscle metabolism using the muscle-GEM. Together with experimental ¹³C-glucose isotopic tracer studies, we identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a rate-limiting enzymatic step in glycolysis in response to HSD. Furthermore, we provided pathway flux analysis to predict additionally perturbed pathways, including fructose and butanoate metabolism, which we validated through metabolite profiling. Altogether, our results represent a significant advance in generating quantitative tissue-specific GEMs in Drosophila and highlight their use for identifying dysregulated metabolic pathways in a human disease model.