Translational evidence of tricarboxylic acid cycle disruptions in obesity: relevance to neuropsychiatric symptoms
Abstract
Obesity is a major public health concern frequently associated with an increased susceptibility to neuropsychiatric symptoms, highlighting the need to elucidate the pathophysiological mechanisms underlying this comorbidity. While converging evidence supports a role for chronic low-grade inflammation, emerging data suggest that additional immunometabolic alterations may also participate, particularly disruptions in mitochondrial tricarboxylic acid (TCA) cycle activity, a central component of cellular energy production. This translational study investigated whether TCA cycle alterations are associated with obesity-related neuropsychiatric symptoms, and whether their associations differ across symptom dimensions. Plasma levels of TCA cycle metabolites were assessed in 83 adults with obesity (BMI > 30 kg/m²), along with depressive (Montgomery-Asberg Depression Rating Scale, MADRS), anxiety (State-Trait Anxiety Inventory, STAI-state form), and fatigue symptoms (Multidimensional Fatigue Inventory, MFI). Concurrently, depressive-like (Sucrose Preference Test, Forced Swim Test) and anxiety-like behaviors (Elevated Plus-Maze) were measured in C57BL/6J male mice chronically exposed to high-fat diet (HFD), together with plasma and brain (striatum, hippocampus, frontal cortex) TCA cycle metabolite levels. Lower circulating metabolite levels were associated with more severe neuropsychiatric symptoms in obese participants, particularly fatigue and reduced motivation. In addition, the preclinical study identified region-specific associations between brain TCA cycle metabolite levels and behavioral outcomes, which may be modulated by HFD exposure. By providing novel evidence linking TCA cycle dysregulation and neuropsychiatric comorbidities in obesity, these findings highlight metabolites of potential interest and suggest that mitochondrial immunometabolic alterations may contribute to obesity-related neuropsychiatric symptoms.
Related
- Halophyte-associated salt-tolerant rhizobacteria: ecological adaptation, mechanistic pathways, and translational relevance for wheat salinity tolerance
- Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research
- Learned Visual Relevance Shapes Perceptual Inference: Evidence from Eyes to Hands
- Effects of Cyclic High Ambient Temperature on Tricarboxylic Acid Cycle Intermediates and Orotate Levels in the Liver and Breast Muscle of Broiler Chickens
- Traditional Mexican Medicinal Plants for Ocular Diseases: Ethnomedicinal Evidence, Pharmacological Relevance, and Research Gaps from Unexplored Sources.
BibTeX
@article{gheorghe2026translational,
title = {{Translational evidence of tricarboxylic acid cycle disruptions in obesity: relevance to neuropsychiatric symptoms}},
author = {Cassandra E. Gheorghe and Juliette Montet and Sylvie Vancassel and Camille Amadieu and Quentin Leyrolle and Sandra Dexpert and Cédric Beau and Damien Forestier and Patrick Ledaguenel and Eric Magne and Nathalie Castanon and Lucile Capuron},
journal = {Translational Psychiatry},
year = {2026},
month = oct,
doi = {10.1038/s41398-026-04476-7},
url = {https://u-bordeaux.hal.science/hal-05778655v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Translational evidence of tricarboxylic acid cycle disruptions in obesity: relevance to neuropsychiatric symptoms
AU - Cassandra E. Gheorghe
AU - Juliette Montet
AU - Sylvie Vancassel
AU - Camille Amadieu
AU - Quentin Leyrolle
AU - Sandra Dexpert
AU - Cédric Beau
AU - Damien Forestier
AU - Patrick Ledaguenel
AU - Eric Magne
AU - Nathalie Castanon
AU - Lucile Capuron
PY - 2026
DA - 2026/10/01
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04476-7
UR - https://u-bordeaux.hal.science/hal-05778655v1
AB - Obesity is a major public health concern frequently associated with an increased susceptibility to neuropsychiatric symptoms, highlighting the need to elucidate the pathophysiological mechanisms underlying this comorbidity. While converging evidence supports a role for chronic low-grade inflammation, emerging data suggest that additional immunometabolic alterations may also participate, particularly disruptions in mitochondrial tricarboxylic acid (TCA) cycle activity, a central component of cellular energy production. This translational study investigated whether TCA cycle alterations are associated with obesity-related neuropsychiatric symptoms, and whether their associations differ across symptom dimensions. Plasma levels of TCA cycle metabolites were assessed in 83 adults with obesity (BMI > 30 kg/m²), along with depressive (Montgomery-Asberg Depression Rating Scale, MADRS), anxiety (State-Trait Anxiety Inventory, STAI-state form), and fatigue symptoms (Multidimensional Fatigue Inventory, MFI). Concurrently, depressive-like (Sucrose Preference Test, Forced Swim Test) and anxiety-like behaviors (Elevated Plus-Maze) were measured in C57BL/6J male mice chronically exposed to high-fat diet (HFD), together with plasma and brain (striatum, hippocampus, frontal cortex) TCA cycle metabolite levels. Lower circulating metabolite levels were associated with more severe neuropsychiatric symptoms in obese participants, particularly fatigue and reduced motivation. In addition, the preclinical study identified region-specific associations between brain TCA cycle metabolite levels and behavioral outcomes, which may be modulated by HFD exposure. By providing novel evidence linking TCA cycle dysregulation and neuropsychiatric comorbidities in obesity, these findings highlight metabolites of potential interest and suggest that mitochondrial immunometabolic alterations may contribute to obesity-related neuropsychiatric symptoms.
SN - 2158-3188
SN - 2158-3188
ER -