Metabolomic Signature of Visceral Adiposity: Insights from a Population-Based Cohort

Background: Visceral adipose tissue (VAT) is a key determinant of cardiometabolic risk, yet its underlying molecular mechanisms remain incompletely characterized. Metabolomics offers an opportunity to identify circulating biomarkers that capture VAT-related biology beyond conventional clinical measures. Methods: We conducted a cross-sectional analysis of 2526 participants from the Qatar Biobank using untargeted serum metabolomics profiling. VAT was quantified using DXA-derived estimates and analyzed both as a continuous variable and by comparing individuals in the highest quartile to the remainder quartiles. Associations between metabolites and VAT were assessed using multivariate partial least squares discriminant analysis and adjusted linear regression models controlling for age, sex, and BMI, with Bonferroni correction for multiple testing. Results: Continuous VAT was associated with 106 metabolites, while the Q4 versus Q1-Q3 contrast identified 23 metabolites, with overlapping metabolites defining a robust core VAT signature. Higher VAT was characterized by coordinated elevation of branched-chain amino acids and their keto/hydroxy acid derivatives, glutamate, and central carbon intermediates, consistent with impaired mitochondrial oxidative decarboxylation. We further identified 4-hydroxyglutamate as a novel collagen-derived metabolite positively associated with VAT, suggesting a potential link between extracellular matrix remodeling and glutamate-centered metabolism. Additionally, greater VAT was associated with lower concentrations of glycine and glycine conjugates and reduced levels of unsaturated sphingomyelins and plasmalogens. Conclusions: These findings provide potential mechanistic insights into VAT-related metabolic dysfunction and identify candidate circulating biomarkers that may enable non-invasive assessment of visceral fat-associated cardiometabolic risk. Longitudinal and mechanistic studies are warranted to establish causality and clinical utility.