# Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels

## TL;DR

This study creates detailed metabolic models for Drosophila tissues and shows how high sugar diets disrupt muscle metabolism.

## Contribution

The study introduces 32 tissue-specific genome-scale metabolic models for Drosophila and applies them to study diet-induced metabolic changes.

## Key findings

- Muscle-specific models reveal altered NAD(H)-dependent reactions and glycolytic flux under high sugar diets.
- 13C-glucose tracing validates decreased glycolytic flux linked to redox modifications.
- High sugar diets cause dysregulation in fructose metabolism pathways in Drosophila muscle.

## Abstract

Individual tissues perform highly specialized metabolic functions to maintain whole-body metabolic homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, modeling tissue-specific metabolism has been limited in this organism. To address this gap, we reconstruct 32 tissue-specific genome-scale metabolic models (GEMs) by integrating a curated Drosophila metabolic network with pseudo-bulk single-nuclei transcriptomics data, revealing distinct metabolic network structures and subsystem coverage across tissues. We validate enriched pathways identified through tissue-specific GEMs, particularly in muscle and fat body, using metabolomics and pathway analysis. Moreover, to demonstrate the utility in disease modeling, we apply muscle-GEM to investigate high sugar diet (HSD)-induced metabolic dysregulation. Constraint-based semi-quantitative flux and sensitivity analyses identify altered NAD(H)-dependent reactions and distributed control of glycolytic flux, including GAPDH. This prediction is further validated through in vivo 13C-glucose isotope tracing study. Notably, decreased glycolytic flux, including GAPDH, is linked to increased redox modifications. Finally, our pathway-level flux analyses identify dysregulation in fructose metabolism. Together, this work establishes a quantitative framework for tissue-specific metabolic modeling in Drosophila, demonstrating its utility for identifying dysregulated reactions and pathways in muscle in response to HSD.

This study develops tissue-specific genome-scale metabolic models for Drosophila and shows how constraint-based flux analyses from the muscle model can identify high sugar diet-induced metabolic dysregulation at reaction and pathway levels.