Abstract
BACKGROUND: The cytosolic 5'-nucleotidase II (NT5C2) enzyme has been implicated in both psychiatric disorders and metabolic traits, but whether these associations reflect a shared biological basis remains unclear. Here we combined cross-species approaches to investigate how reduced NT5C2 function shapes behavior. RESULTS: In Drosophila melanogaster, neuronal knockdown of the ortholog dNT5B increased activity around light-dark transitions, reduced sleep fragmentation, and selectively suppressed food intake under satiated conditions. Moreover, analysis of mouse phenotyping data revealed that whole-body Nt5c2 knockout alters locomotor activity, sensorimotor gating, and anxiety-related behaviors. Finally, human variant-trait associations showed reproducible enrichment in both metabolic domains, including body composition and BMI, and neuro-psychiatric outcomes such as schizophrenia, smoking, and anxiety. CONCLUSIONS: Together, these phenotypic findings indicate that NT5C2 is a conserved neuro-metabolic regulator, linking energy-related pathways to specific behavioral dimensions that may underlie its pleiotropic impact on psychiatric and metabolic risk.