Regulation of feeding and metabolism by fat mass and obesity-associated protein in zebrafish

The fat mass and obesity-associated (FTO) gene has been widely implicated in the regulation of energy balance in mammals. Whether FTO has similar roles in non-mammals remains unexplored. The goal of this research was to determine if FTO inhibition affects feeding, metabolism and lipid homeostasis in zebrafish (Danio rerio). Rhein, a pharmacological inhibitor of FTO was used to examine if FTO suppression modulates metabolic pathways in zebrafish liver and brain in vivo, and in zebrafish liver (ZFL) cells in vitro. Rhein treatment resulted in a significant reduction in food intake, accompanied by corresponding downregulation of FTO and its downstream effector IRX3 at both the mRNA and protein levels. Inhibiting FTO upregulated lipid oxidation genes and downregulated lipogenic pathways, indicating enhanced lipid catabolism. Moreover, rhein administration elevated key metabolic regulators AMPK and PPARα while suppressing gluconeogenic genes, suggesting improved glucose homeostasis. These findings suggest that FTO plays an important role in zebrafish metabolic regulation and that its inhibition modulates energy balance via the STAT3 signaling pathway. This research provides insights into the evolutionary conservation of FTO function and further supports FTO as a key molecule in zebrafish metabolic regulation.