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Abstract

Summary— Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. To acquire a more detailed understanding of the biochemical pathways, we applied high-throughput metabolite profiling to samples from 1761 individuals from 2 large, well-characterized clinical cohorts. We observed that the presence of metabolic risk factors (including obesity, insulin resistance, high blood pressure, and dyslipidemia) was significantly associated with variation in select metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed particularly strong associations of insulin resistance traits with decreased glutamine and increased glutamate. We followed up these findings in experimental models and demonstrated that glutamine administration in mice resulted in both increased glucose tolerance and decreased blood pressure. Taken together, our clinical and experimental data highlight the glutamine-glutamate metabolic pathway as a potential target for interventions aimed at attenuating metabolic risk in humans. Furthermore, by demonstrating the feasibility and utility of biochemical profiling in large clinical samples, we anticipate that our data could serve as a resource for future studies of the human metabolome and its relevance to cardiovascular and metabolic diseases. Because metabolites represent intermediate traits that may play functional roles (either adaptive or maladaptive) in disease pathogenesis, future applications of metabolomics technology can provide additional insights into the mechanisms by which established risk factors are associated with clinically important outcomes. Conclusions— Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.1 Summary— Recent confirmation that in addition to white adipose tissue, brown adipose tissue (BAT) is found in adult humans, where it plays a distinct …