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

Nathalie Castanon, Sylvie Vancassel, Camille Amadieu, Sofia Cussotto, Quentin Leyrolle, Céline Lucas, Antoine Lefevre, Patrick Emond, Anne-Laure Dinel, Lucile Capuron
Brain, Behavior, and Immunity. 2025-11-01; 130: 106107
DOI: 10.1016/j.bbi.2025.106107

PubMed

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https://www.bordeaux-neurocampus.fr/12579

Castanon N(1), Vancassel S(2), Amadieu C(2), Cussotto S(3), Leyrolle Q(2), Lucas C(4), Lefevre A(5), Emond P(5), Dinel AL(4), Capuron L(2).

Author information:
(1)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France. Electronic address: .
(2)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France.
(3)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France; Univ. Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé
des Populations (CESP), UMR 1018, CESP-Inserm, Team Moods, 91400 Orsay, France.
(4)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux,
France; NutriBrain Research and Technology Transfer, NutriNeuro, F-33000
Bordeaux, France.
(5)INSERM, Univ. Tours, Imaging Brain & Neuropsychiatry (iBraiN), UMR 1253,
37000 Tours, France; Plateforme de Métabolomique et d’Analyses Chimiques, US-61
ASB, Univ. Tours, CHRU Tours, INSERM, 37000 Tours, France.

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.