Multiplatform metabolomics for an integrative exploration of metabolic syndrome in older men

Abstract

Background Metabolic syndrome (MetS), a cluster of factors associated with risks of developing cardiovascular diseases, is a public health concern because of its growing prevalence. Considering the combination of concomitant components, their development and severity, MetS phenotypes are largely heterogeneous, inducing disparity in diagnosis. Methods A case/control study was designed within the NuAge longitudinal cohort on aging. From a 3-year follow-up of 123 stable individuals, we present a deep phenotyping approach based on a multiplatform metabolomics and lipidomics untargeted strategy to better characterize metabolic perturbations in MetS and define a comprehensive MetS signature stable over time in older men. Findings We characterize significant changes associated with MetS, involving modulations of 476 metabolites and lipids, and representing 16% of the detected serum metabolome/lipidome. These results revealed a systemic alteration of metabolism, involving various metabolic pathways (urea cycle, amino-acid, sphingo- and glycerophospholipid, and sugar metabolisms…) not only intrinsically interrelated, but also reflecting environmental factors (nutrition, microbiota, physical activity…). Interpretation These findings allowed identifying a comprehensive MetS signature, reduced to 26 metabolites for future translation into clinical applications for better diagnosing MetS.

Oxylipin profiling identifies a mechanistic signature of metabolic syndrome: results from two independent cohorts

“…Contrary to previous studies using data-driven approaches (8,34), we have targeted a specific class of lipid mediators, namely oxylipins, which were hypothetized as being potential biologically relevant and integrative biomarkers of the molecular pathways of MetS. Our hypothesis-driven approach was combined with a high-throughput methodology allowing the quantitative profiling of over 130 different oxylipins.…”

“…Over the last decades, metabolomics and lipidomics have emerged as very relevant and powerful tools to capture the complexity of cardiometabolic disturbances and to inform on underlying mechanisms (6). Contrary to previous studies using data-driven approaches (8, 34), we have targeted a specific class of lipid mediators, namely oxylipins, which were hypothetized as being potential biologically relevant and integrative biomarkers of the molecular pathways of MetS. Our hypothesis-driven approach was combined with a high-throughput methodology allowing the quantitative profiling of over 130 different oxylipins.…”

“…In the Discovery and Replication studies, the oxylipin signature suggested the implementation of compensatory mechanism of the cardiometabolic disturbances in the MetS participants that could be impaired with age. The oxylipin signature of MetS is also original with regards to another MetS signature recently identified using untargeted metabolomics (8). Indeed, this approach does not allow the detection of oxylipins and rather informs on the most abundant circulating metabolites.…”

“…Moreover, the partial mapping of the metabolome and annotation uncertainties limit biological interpretation (8). To face this limitation while keeping a systemic approach, we have targeted a specific class of lipid mediators called oxylipins (including eicosanoids) arising from the oxygenation of polyunsaturated fatty acids (PUFAs) through the coordinated action of over 50 unique and cell-specific enzymes (9).…”

“…However, the coverage of untargeted assays is often limited to the most abundant metabolites (such as building blocks of cell membrane and “fuel” metabolites involved in energy production and storage) and does not inform on signaling metabolites that are present at lower concentrations (7). Moreover, the partial mapping of the metabolome and annotation uncertainties limit biological interpretation (8). To face this limitation while keeping a systemic approach, we have targeted a specific class of lipid mediators called oxylipins (including eicosanoids) arising from the oxygenation of polyunsaturated fatty acids (PUFAs) through the coordinated action of over 50 unique and cell-specific enzymes (9).…”