Urinary metabolic signatures of human adiposity

In a large-scale population-based metabolic phenotyping study, diverse sets of urinary metabolites, including gut microbial co-metabolites, were reproducibly associated with human adiposity. Urinary metabolites and adiposity Elliott et al. examined urinary metabolites over two 24-hour time periods in a large epidemiological study of obese individuals in the United States and UK. The urinary metabolites that were associated with adiposity were related to renal function, gut microbial metabolism, energy metabolism, skeletal muscle metabolism, branched-chain amino acid metabolism, and dietary intake. The urinary excretion patterns were reproducible over time and across the U.S. and UK population cohorts. Together, the metabolites described the metabolic disturbances of adiposity and were visualized in a metabolic reaction network. The network showed unforeseen dependencies and interconnectivities of biochemical pathways that were perturbed in adiposity and pointed to the collective importance of metabolism, diet, environment, and life-style in the ongoing obesity epidemic. Obesity is a major public health problem worldwide. We used 24-hour urinary metabolic profiling by proton (1H) nuclear magnetic resonance (NMR) spectroscopy and ion exchange chromatography to characterize the metabolic signatures of adiposity in the U.S. (n = 1880) and UK (n = 444) cohorts of the INTERMAP (International Study of Macro- and Micronutrients and Blood Pressure) epidemiologic study. Metabolic profiling of urine samples collected over two 24-hour time periods 3 weeks apart showed reproducible patterns of metabolite excretion associated with adiposity. Exploratory analysis of the urinary metabolome using 1H NMR spectroscopy of the U.S. samples identified 29 molecular species, clustered in interconnecting metabolic pathways, that were significantly associated (P = 1.5 × 10−5 to 2.0 × 10−36) with body mass index (BMI); 25 of these species were also found in the UK validation cohort. We found multiple associations between urinary metabolites and BMI including urinary glycoproteins and N-acetyl neuraminate (related to renal function), trimethylamine, dimethylamine, 4-cresyl sulfate, phenylacetylglutamine and 2-hydroxyisobutyrate (gut microbial co-metabolites), succinate and citrate (tricarboxylic acid cycle intermediates), ketoleucine and the ketoleucine/leucine ratio (linked to skeletal muscle mitochondria and branched-chain amino acid metabolism), ethanolamine (skeletal muscle turnover), and 3-methylhistidine (skeletal muscle turnover and meat intake). We mapped the multiple BMI-metabolite relationships as part of an integrated systems network that describes the connectivities between the complex pathway and compartmental signatures of human adiposity.