Zebrafish as a translational model for peptide-mediated synaptic dysfunction related to obesity.

Obesity-driven synaptic dysfunction is increasingly recognized as a key mechanism linking metabolic disorders to neurodegenerative diseases. This review aims to explore the utility of zebrafish (Danio rerio) as a translational model to investigate these mechanisms and screen peptide-based therapeutic strategies. Owing to their optical transparency, genetic tractability, and suitability for high-throughput screening, zebrafish provide a powerful platform for studying neuronal circuitry and evaluating bioactive peptides in vivo. Current evidence on pathophysiological processes underlying obesity-related synaptic impairment, including central resistance to metabolic hormones, oxidative stress, and the chronic inflammatory state, which promotes persistent immune activation and neuroinflammation. In addition, the persistence of these disturbances in the organism can lead to dysfunctions and pathologies, such as Parkinson's and Alzheimer's diseases, both of which are discussed in more detail in this review. Also, particular emphasis is placed on the roles of glial cells and the gut-brain axis in modulating synaptic integrity. We highlight how cutting-edge technologies, such as live neural imaging and single-cell transcriptomics, are accelerating peptide discovery and mechanism-of-action studies in zebrafish. Furthermore, we discuss emerging therapeutic peptides such as GLP-1 analogs and BDNF-based molecules that modulate inflammatory pathways, restore insulin signaling, and enhance neuronal resilience. Collectively, the evidence positions zebrafish as a robust model not only for elucidating disease mechanisms but also for advancing peptide-based interventions targeting synaptic dysfunction in obesity.