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CONTEXT: There is a dispute whether obesity without major metabolic derangements may represent a benign condition or not.

OBJECTIVE: We aimed to compare the plasma metabolome in obese subjects without the metabolic syndrome (MetS) to normal-weight subjects without MetS, as well as to obese subjects with MetS.

DESIGN: Cross-sectional.

SETTING: Two academic centers in Sweden.

PARTICIPANTS: Three population-based samples (EpiHealth, n=2342, SCAPIS-Uppsala, n=4985 and SCAPIS-Malmö, n=3978) in which individuals were divided into groups according to their BMI and presence/absence of MetS (NCEP/consensus criteria).

INTERVENTION: None.

MAIN OUTCOME MEASURE: 791 annotated endogenous metabolites measured by ultra-performance liquid chromatography tandem mass spectrometry.

RESULTS: We observed major differences in metabolite profiles (427 metabolites) between obese (BMI ≥ 30 kg/m 2) and normal-weight (BMI < 25 kg/m 2) subjects without MetS after adjustment for major life-style factors. Pathway enrichment analysis highlighted branch-chained and aromatic amino acid synthesis/metabolism, aminoacyl-tRNA biosynthesis and sphingolipid metabolism. The same pathways, and similar metabolites, were also highlighted when obese subjects with and without MetS were compared despite adjustment for BMI and waist circumference, or when the metabolites were related to BMI and number of MetS components in a continuous fashion. Similar metabolites and pathways were also related to insulin sensitivity (Matsuda index) in a separate study (POEM, n=501).

CONCLUSION: Our data suggest a graded derangement of the circulating metabolite profile from lean to obese to the metabolic syndrome, in particular for metabolites involved in amino acid synthesis/metabolism and sphingolipid metabolism. Insulin resistance is a plausible mediator of this gradual metabolic deterioration.