Inhibition of the translin/trax complex by ellagic acid alleviates metabolic and affective behaviors in obese male mice.

Obesity is frequently associated with depression and anxiety, yet the molecular mechanisms linking metabolic dysfunction to affective disturbances remain incompletely understood. We previously showed that genetic deletion of Translin induces obesity while increasing circulating adiponectin without exacerbating adipose or hepatic inflammation. Here, we demonstrate that Translin knockout markedly reduces anxiety- and depression-like behaviors in male mice compared with wild-type controls, despite no significant alterations in monoaminergic neurotransmitters, suggesting a monoamine-independent mechanism. We further identify the Translin/Trax (TN/TX) complex as a direct molecular target of ellagic acid (EA), a dietary polyphenol. Structural and biochemical analyses revealed that EA binds TN/TX and suppresses its miRNA-degrading RNase activity without disrupting RNA binding. In high-fat diet-induced obese male mice, pharmacological inhibition of TN/TX by EA (100 mg/kg) recapitulated and extended the genetic phenotype, significantly reducing systemic inflammation, improving glucose tolerance and insulin sensitivity, and alleviating anxiety- and depression-like behaviors. Collectively, these findings identify TN/TX as a targetable molecular hub linking metabolic inflammation to affective regulation and suggest EA as a potential small-molecule modulator for obesity-associated metabolic and mood disorders.