Urinary metabolic signatures of human adiposity.
Obesity is a major public health problem worldwide. We used 24-hour urinary metabolic profiling by proton ((1)H) 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 (1)H 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.
Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England (MRC-PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. p.elliott@imperial.ac.uk j.nicholson@imperial.ac.uk.
Paul
P
Elliott
Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England (MRC-PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Joram M
JM
Posma
Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England (MRC-PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
Queenie
Q
Chan
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Isabel
I
Garcia-Perez
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Anisha
A
Wijeyesekera
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Magda
M
Bictash
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Timothy M D
TM
Ebbels
Department of Health Science, Shiga University of Medical Science, Otsu 520-2192, Japan.
Hirotsugu
H
Ueshima
Department of Epidemiology, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing, Beijing 100037, People's Republic of China.
Liancheng
L
Zhao
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Linda
L
van Horn
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. College of Medicine at Chicago, University of Illinois at Chicago, Chicago, IL 60612, USA.
Martha
M
Daviglus
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Jeremiah
J
Stamler
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
Elaine
E
Holmes
Biomolecular Medicine, Division of Computational and Systems Medicine, MRC-National Institute for Health Research (MRC-NIHR) National Phenome Centre, MRC-PHE Centre for Environment and Health, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. p.elliott@imperial.ac.uk j.nicholson@imperial.ac.uk.
Jeremy K
JK
Nicholson
D050154:Adiposity; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D015992:Body Mass Index; D004734:Energy Metabolism; D006801:Humans; D055432:Metabolomics; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000652:urine; D066244:Proton Magnetic Resonance Spectroscopy
D000597:Amino Acids, Branched-Chain