Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes.

ABSTRACT:

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 vs 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 < 4.5 × 10−4). 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.

SUBMITTER: Yin X 

PROVIDER: S-EPMC4880163 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature