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.
Neuronal knockdown of the Drosophila NT5C2 ortholog dNT5B increased locomotor activity around light-dark transitions.
Neuronal knockdown of dNT5B reduced sleep fragmentation in Drosophila.
Neuronal knockdown of dNT5B selectively suppressed food intake under satiated conditions in Drosophila.
Whole-body Nt5c2 knockout in mice alters locomotor activity, sensorimotor gating, and anxiety-related behaviors.
Human NT5C2 variant-trait associations showed reproducible enrichment in both metabolic and neuro-psychiatric domains.
NT5C2 function is conserved across Drosophila, mouse, and human in regulating neuro-metabolic behaviors.
This research suggests that a gene called NT5C2, which produces an enzyme involved in cellular energy metabolism, plays a conserved role in regulating both behavior and metabolism across multiple species. By studying fruit flies with reduced activity of the equivalent gene (dNT5B) specifically in nerve cells, researchers found that these flies were more active around the time lights switched on and off, slept more consolidatedly (less fragmented sleep), and ate less when they were already full. In mice completely lacking the Nt5c2 gene, multiple behavioral changes were observed including altered movement, impaired sensorimotor gating (a measure relevant to conditions like schizophrenia), and changes in anxiety-like behavior. In humans, genetic variants in the NT5C2 region were statistically associated with both metabolic traits — such as body composition and body mass index — and psychiatric or behavioral outcomes — including schizophrenia, smoking behavior, and anxiety. These associations appeared consistently across analyses, suggesting they are not coincidental. The findings matter because they suggest that the well-known but poorly understood connections between psychiatric disorders and metabolic conditions like obesity may partly share a biological root in NT5C2 function. This research points to NT5C2 as a potential bridge between brain-based behavioral regulation and body-wide energy metabolism, which could inform future research into why psychiatric and metabolic diseases so often occur together in the same individuals.
Moulin T, Aldavero-Muñoz I, Williams M, Schiöth H. (2026). Conserved NT5C2 links context-specific behaviors with psychiatric and metabolic risk.. Behavioral and brain functions : BBF. https://doi.org/10.1186/s12993-025-00314-w