Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes

Context: Metabolic dysregulation underlies key metabolic risk factors—obesity, dyslipidemia, and dysglycemia. Objective: To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor changes over time. Design: Cross-sectional—discovery samples (N=650; age=36–69 years) from the Framingham Heart Study (FHS) and replication samples (N=670; age=61–76 years) from the BioImage Study, both following a factorial design sampled from high versus low strata of body mass index, lipids, and glucose. Longitudinal—FHS participants (N=554) with 5–7 years of follow-up for risk factor changes. Setting: Observational studies. Participants: Cross-sectional samples with or without obesity, dysglycemia, and dyslipidemia, excluding prevalent cardiovascular disease and diabetes or dyslipidemia treatment. Age and sex matched by group. Interventions: None. Main Outcome Measure(s): Gas chromatography-mass spectrometry detected 119 plasma metabolites. Cross-sectional associations with obesity, dyslipidemia, and dysglycemia were tested in discovery, with external replication of 37 metabolites. Single- and multi-metabolite markers were tested for association with longitudinal changes in risk factors. Results: Cross-sectional metabolite associations were identified with obesity (n=26), dyslipidemia (n=21), and dysglycemia (n=11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (p<4.5x10–4). Metabolites associated with longitudinal risk factor changes were enriched for bioactive lipids. Multi-metabolite panels explained 2.5–15.3% of longitudinal changes in metabolic traits. Conclusions: Cross-sectional results implicated dysregulated glutamate cycling and amino acid metabolism in metabolic risk. Certain bioactive lipids were associated with risk factors cross-sectionally and over time, suggesting their upstream role in risk factor progression. Functional studies are needed to validate findings and facilitate translation into treatments or preventive measures.