The metabolomic profiling of total fat and fat distribution in a multi-cohort study of women and men

Currently studies aiming for the comprehensive metabolomics profiling of measured total fat (%) as well as fat distribution in both sexes are lacking. In this work, bioimpedance analysis was applied to measure total fat (%) and fat distribution (trunk to leg ratio). Liquid chromatography-mass spectrometry-based untargeted metabolomics was employed to profile the metabolic signatures of total fat (%) and fat distribution in 3447 participants from three Swedish cohorts (EpiHealth, POEM and PIVUS) using a discovery-replication cross-sectional study design. Total fat (%) and fat distribution were associated with 387 and 120 metabolites in the replication cohort, respectively. Enriched metabolic pathways for both total fat (%) and fat distribution included protein synthesis, branched-chain amino acids biosynthesis and metabolism, glycerophospholipid metabolism and sphingolipid metabolism. Four metabolites were mainly related to fat distribution: glutarylcarnitine (C5-DC), 6-bromotryptophan, 1-stearoyl-2-oleoyl-GPI (18:0/18:1) and pseudouridine. Five metabolites showed different associations with fat distribution in men and women: quinolinate, (12Z)-9,10-dihydroxyoctadec-12-enoate (9,10-DiHOME), two sphingomyelins and metabolonic lactone sulfate. To conclude, total fat (%) and fat distribution were associated with a large number of metabolites, but only a few were exclusively associated with fat distribution and of those metabolites some were associated with sex*fat distribution. Whether these metabolites mediate the undesirable effects of obesity on health outcomes remains to be further investigated.