Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes.

WILLINGER CM; COURCHESNE P; HWANG SJ; YIN X; MUNTENDAM P; CHEN G; SOOKOIAN S; CHEN BH; ADOURIAN A; FOX CS; FUSTER V; PIROLA CJ; SUBRAMANIAN S; LARSON MG; JUHASZ P; LI X; O'DONNELL CJ; BOBELDIJK-PASTOROVA I; GORDON N; LEVY D

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2016 vol. 101 p. 1779 - 1789

0021-972X

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 (N650; age36?69 years) from the Framingham Heart Study (FHS) and replication samples (N670; age61?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 articipants (N554) 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 (n26), dyslipidemia(n21), and dysglycemia (n11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (p4.5x10?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.