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

Abstract

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.

The authors' abstract, as published at the source. Translational Psychiatry, 2026 · DOI ↗