Homeostatic Counter‐Regulation Mediates Spermidine‐Induced Triacylglyceride Reduction in <i>Drosophila melanogaster</i> —From Phenotype to Molecular Mechanism

The polyamines putrescine, spermidine (Spd), and spermine have essential functions in cell growth and proliferation. Previous research has unveiled a potential link between polyamine metabolism and triacylglyceride (TAG) homeostasis. In this study, we utilized Drosophila melanogaster as a model to study the impact of dietary (Spd) on body TAG stores. We found that food supplementation with 1.0 mM and 2.5 mM Spd prevented the build-up of TAG stores in female fruit flies monitored for up to 14 days post-eclosion in a dose- and time-dependent manner, without affecting their total protein content. Notably, a 7-day treatment with 2.5 mM Spd also counteracted high-sugar diet-induced obesity and accelerated the breakdown of existing TAG reserves in obese females. Mechanistic analysis revealed that the adipokinetic hormone (Akh) pathway but not the TAG lipase Brummer (Bmm) was required for the TAG-lowering bioactivity of Spd. Remarkably, this TAG-reducing activity was completely abolished when flies were fed a high-yeast diet, which increases dietary protein. Analyses of the polyamine pattern of flies and their excreta revealed that under low dietary yeast conditions, the administered Spd did not result in a rise in the endogenous Spd level. Instead, the Spd metabolites putrescine and N¹-acetylated Spd were increased, which provides evidence for the induction of the catabolic arm of the polyamine pathway. Together, our data suggest that the administration of Spd at lower mM concentrations, if combined with a low-protein diet, stimulates Akh-dependent catabolic processes that facilitate the reduction of fat stores in D. melanogaster. This work uncovers a diet-dependent metabolic role of Spd in fat storage regulation, which awaits confirmation in mammals and humans, and highlights the importance of nutrient context in modulating polyamine-mediated metabolic outcomes.