Translational evidence of tricarboxylic acid cycle disruptions in obesity: relevance to neuropsychiatric symptoms

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. We would like to thank Dr M.

Duvivier, and medical assistants for their valuable support in patients’ recruitment, A-L. Lucas for their help with preclinical experiments, and the NutriNeuro’s staff from the CIRCE (Behavioral Engineering Centre) Facility of Bordeaux Neurocampus for animal care. Quantification of TCA cycle metabolites was performed at the Plateforme Scientifique et Technique d’Analyse des Systèmes Biologiques (PST-ASB) of Tours University.

This work was supported by funds from the French National Research Institute for Agriculture, Food and Environment (INRAE), grants from the JPI HDHL Biomarkers for Nutrition and Health (HEALTHMARK, French National Research Agency: ANR-16-HDHL-0003-03, LC; ANR-11-JSV1-0006, LC), and the Marcel Dassault Prize for Research in Mental Disorders (Fondation FondaMental, LC). These authors contributed equally: Cassandra E. Gheorghe, Juliette Montet.

These authors jointly supervised this work: Nathalie Castanon, Lucile Capuron. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France Cassandra E. Gheorghe, Juliette Montet, Sylvie Vancassel, Camille Amadieu, Quentin Leyrolle, Sandra Dexpert, Nathalie Castanon & Lucile Capuron Service de Chirurgie Digestive et Pariétale, Clinique Tivoli, 33000 Bordeaux, and Clinique Jean Villar, 33520, Bruges, France Cédric Beau, Damien Forestier, Patrick Ledaguenel & Eric Magne Correspondence to Nathalie Castanon or Lucile Capuron.