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The Metabolic Phenotype of Obesity in a Saudi Population MUHAMMAD Saeed AHMAD, Munirah Alsaleh, Torben Kimhofer, Sultan Ahmad, Wisam Jamal, Siraj Omar Wali, Jeremy Kirk Nicholson, Zoheir Abdullah Damanhouri, and Elaine Holmes J. Proteome Res., Just Accepted Manuscript • DOI: 10.1021/acs.jproteome.6b00710 • Publication Date (Web): 14 Dec 2016 Downloaded from http://pubs.acs.org on December 16, 2016
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Journal of Proteome Research
The Metabolic Phenotype of Obesity in a Saudi Population Muhammad Saeed Ahmada, Munirah Alsalehb, Torben Kimhoferb, Sultan Ahmada, Wisam Jamalc, Siraj Omar Walid, Jeremy Kirk Nicholsonb, Zoheir Abdullah Damanhouria, e, Elaine Holmesa, b*
a
Drug Metabolism Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah,
21589, Saudi Arabia b
Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College
London, South Kensington, London SW7 2AZ, UK c
Department of Surgery, Faculty of Medicine, University of Jeddah, Jeddah, 21589, Saudi Arabia
d
Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589,
Saudi Arabia e
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589,
Saudi Arabia
KEYWORDS: Obesity, Metabolic profiling, Metabonomics, NMR.
Disclosure Statement: All Authors have nothing to disclose.
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Abstract
Metabolic phenotyping of obese populations can shed light on understanding environmental interactions underpinning obesogenesis. Obesity and its comorbidities are a major health and socioeconomic concern globally and are highly prevalent in the Middle East. We employed nuclear magnetic resonance spectroscopy (NMR) to characterise the metabolic signature of urine and blood plasma for a cohort of (n=50) obese compared to non-obese Saudi participants (n=48). The urinary metabolic phenotype of obesity was characterised by higher concentrations of N-acetyl glycoprotein fragment, bile acids, lysine and methylamines and lower concentrations of tricarboxylic acid cycle intermediates, glycine and gut microbial metabolites. The plasma metabolic phenotype of obesity was dominated by sugars, branched chain amino acids and lipids, particularly unsaturated lipids, with lower levels of plasma phosphorylcholine and HDL. Serum hepatic enzymes, triglycerides and cholesterol mapped to specific metabolic phenotypes, potentially indicating multiple distinct obesityrelated pathway dysregulation. Differences between urine and plasma phenotypes of obesity for this Saudi population and that reported for Caucasian individuals indicate population disparities in pathways relating to ketogenesis (more apparent in the Saudi obese population), dysregulated liver function and the gut microbiome. Mapping population-specific metabolic perturbations may hold promise in establishing population differences relevant to disease-risk and stratification of individuals with respect to discovery of new therapeutic targets.
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Introduction The prevalence of obesity and its comorbidities in the Middle East is accelerating 1. According to a recent report, 69% of men aged 20 years or older are overweight, compared to 74.2% of women of similar age in Saudi Arabia 2. Obesity-associated conditions such as diabetes, which increased from 10.6% in 1989 to 32.1% in 2009 in Saudi Arabia3, cardiovascular disease, sleep apnoea and idiopathic intracranial hypertension (IIH) have been studied in Middle Eastern populations but as yet there are relatively few studies reporting the complex metabolic phenotypes associated with obesity.
The true aetiology of obesity remains to be fully elucidated but is almost certainly a product of geneenvironment interactions. The socioeconomic shift in Saudi Arabia and other Gulf countries has resulted in adoption of Westernised diets, which are typically high in fats and sugars and low in vegetables and fibre, and a reliance on migrant workers and service industries with a corresponding decline in the levels of physical activity 4-5. Although several studies point to the influence of genetic determinants of body weight and obesity, genes explain only a small fraction of the BMI population variance, constituting a 1.8-fold obesity risk in adults 6. The two best known gene examples that have been associated with an obese phenotype, being the FTO and MC4R genes, and although there is consensus that the FTO gene is important in modulating obesity, its exact association is complex and it is thought that at least some part of the association is mediated by neighboring genes RPGRIP1L and IRX3 7.
Metabolic phenotyping using nuclear magnetic resonance (NMR) or mass-spectrometry (MS) based spectral profiling has been used to explore the impact of gene-environment interactions in human populations and to characterise the metabolic phenotype associated with obesity8-10. Although application of metabolic profiling in understanding obesity and related conditions is gaining support in the Gulf Co-operation Council countries 11, there are sparse reports about metabolic profiling in the region, and none for Saudi Arabia.
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We apply an NMR-based metabolic profiling strategy to characterise the plasma and urine metabolomes associated with obesity in participants living in Saudi Arabia and to identify components of those metabolic signatures associated with clinical correlates such as blood triglyceride levels and liver function enzymes, comparing the outcomes to published data on American and European populations.
Materials and methods Study design and data collection The study was approved by the research ethics committee of King Abdulaziz University (KAU), Jeddah, Saudi Arabia. Written informed consent was obtained from all participants prior to inclusion and participants aged between 18-40 years were enrolled for the study. People with BMI
