In:
The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 101, No. 4 ( 2016-04-01), p. 1779-1789
Abstract:
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 & lt; 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.
Type of Medium:
Online Resource
ISSN:
0021-972X
,
1945-7197
DOI:
10.1210/jc.2015-2555
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2016
detail.hit.zdb_id:
2026217-6
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