Partial Serotonin Transporter Deficiency Modulates Plasma Metabolome, Arginine-Nitric Oxide Pathway and Emotional Behavior in Mice Exposed to Western Diet

<b>Background/Objectives</b>: Reduced serotonin transporter (SERT) function is associated with increased vulnerability to emotional and metabolic dysregulation, particularly in elderly women. Most preclinical studies relied on young male rodents with complete <i>Sert</i> deficiency; the Western diet (WD) acerbates these abnormalities. However, complete <i>Sert</i> loss does not fully reflect the human condition of partial SERT dysfunction. Here, we examined the effects of WD in aged female Sert^+/- mice on metabolic, biochemical, molecular, and behavioral outcomes. <b>Methods:</b> Wild-type (WT) and Sert^+/- mice were fed WD or a control diet. Emotionality, cognition, glucose tolerance (GT), plasma ¹HNMR spectroscopy metabolome and biochemical parameters were studied. Gene expression analyses of nitric oxide (NO)-related markers were performed in the hypothalamus, dorsal raphe, and liver. <b>Results:</b> WD-exposed WT mice showed impaired GT and reduced plasma lactate and branched-chain amino acid levels; metabolome changes were more pronounced in mutants, while GT was unchanged. Naïve Sert^+/- mice exhibited lower lactate and alanine levels compared with WT controls. WD increased leptin and cholesterol levels in both genotypes, whereas triglyceride concentrations were reduced in Sert^+/- mice. Both WD and <i>Sert</i> deficiency increased <i>Nos</i> expression, while arginase expression was differentially regulated by genotype and diet. Malondialdehyde levels were elevated in the prefrontal cortex of Sert^+/- mice regardless diet. WD also impaired object recognition memory and induced anxiety- and depression-like behaviors, with more pronounced effects in Sert^+/- mice, except marble test behavior. <b>Conclusions:</b> Partial <i>Sert</i> deficiency aggravates some but not all WD-induced metabolic alterations, enhances oxidative stress, dysregulates arginine-NO signaling, and modifies behavior, highlighting the translational relevance of Sert^+/- mice for modeling SERT dysfunction.