Metabolomic Pathways Distinguishing Metabolically Healthy and Unhealthy Obesity from Normal-Weight: A Cross-Sectional Study

Metabolic health extends beyond BMI: some obese individuals remain metabolically resilient, while many normal-weight individuals exhibit hidden dysfunction. In Qatar, where obesity and metabolic disorders are widespread, understanding these divergent phenotypes is clinically paramount. This study maps the circulating metabolites and biological pathways associated with metabolic dysfunction. Clinical data from 6000 adults in the Qatar Biobank were used to determine obesity prevalence and classify metabolic health status among individuals with normal-weight and obese individuals. Comprehensive statistical analyses were conducted to determine associations between metabolic phenotypes and clinical parameters. Untargeted plasma metabolomics were performed in a subset of participants. Differential metabolite expression and pathway enrichment analyses were conducted to identify the distinct metabolic signatures underlying metabolic health. Mean age ranged from 30.9 ± 11.3 years in metabolically healthy normal-weight (MHNW) individuals to 46.0 ± 10.9 years in metabolically unhealthy obese (MUHO) individuals, with females predominating in the MHO group (65.2%). MUHO participants had higher rates of diabetes (21%), hypertension (34.7%), and insulin resistance (96.8%). Elevated C-peptide, uric acid, ferritin, and inflammatory markers were positively associated with metabolic unhealthiness, particularly in obese females, whereas estradiol and free thyroxine showed protective associations. Metabolomic profiling revealed distinct lipid and amino acid signatures differentiating MHO, MUHO, and MHNW phenotypes, with pathway analysis highlighting disruptions in lipid metabolism, amino acid pathways, and membrane transport. Metabolic heterogeneity in obesity reflects differences in coordinated biochemical regulation rather than adiposity alone. Identified metabolite signatures and ratios may serve as biomarkers of metabolic resilience and early risk stratification.