Obesity-induced emotional alterations in mice are associated with impairments of tryptophan metabolism along the kynurenine and indole pathways.

Chronic inflammatory conditions, such as obesity, are frequently associated with a high prevalence of mood disorders and a reduced response to conventional antidepressants. Therefore, identifying the biological substrates underlying these comorbidities is crucial, as it could help uncover new therapeutic strategies to improve current treatments. Growing evidence implicates inflammation-driven dysregulation of tryptophan breakdown along the kynurenine pathway (KP) as a key contributor, although the specific roles of its various metabolites remain unclear. Additionally, the involvement of the gut-derived indole pathway (IP) of tryptophan metabolism is still poorly understood, despite increasing evidence linking gut microbiota metabolites to mood regulation. To address these questions, we assessed depressive-like and anxiety-like behaviors in C57BL/6J mice chronically exposed to high-fat diet (HFD), a reliable preclinical model of inflammatory depression. We also measured plasma and brain (hippocampus, frontal cortex, striatum) levels of a broad panel of KP and IP metabolites. HFD increased emotional behaviors and altered plasma and brain levels of tryptophan metabolites. Notably, it promoted a systemic neurotoxic-neuroprotective KP imbalance favoring neurotoxicity. It also drastically reduced indole production, with significant repercussions on brain indole-3 sulfate levels. Importantly, these metabolomic changes correlated with the severity of emotional alterations, with distinct metabolite-behavior relationships depending on the specific neuropsychiatric symptom dimensions assessed. In conclusion, this study offers valuable novel insights into the role of KP- and IP-derived tryptophan metabolites as key mediators between obesity and depression, and thus potential new promising therapeutic targets to improve neuropsychiatric comorbidities of obesity.