Metabolomics Profiling of Visceral Adipose Tissue: Results From MESA and the NEO Study

Ian J. Neeland*, Sebastiaan C. Boone, Dennis O. Mook-Kanamori, Colby Ayers, Roelof A.J. Smit, Ioanna Tzoulaki, Ibrahim Karaman, Claire Boulange, Dhananjay Vaidya, Naresh Punjabi, Matthew Allison, David M. Herrington, J. Wouter Jukema, Frits R. Rosendaal, Hildo J. Lamb, Ko Willems van Dijk, Philip Greenland, Renée de Mutsert

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background: Identifying associations between serum metabolites and visceral adipose tissue (VAT) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT. Methods and Results: Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT (P=4.88×10−20–1.16×10−3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT (P=1.90×10−35–8.46×10−7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions: We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

Original languageEnglish (US)
Article numbere010810
JournalJournal of the American Heart Association
Volume8
Issue number9
DOIs
StatePublished - May 7 2019

Funding

Dr Neeland has received honoraria, consulting and speaker’s bureau fees, and travel support from Boehringer-Ingelheim/ Lilly Alliance (significant), has received a research grant from Novo Nordisk (significant), and is a member of the scientific advisory board of AMRA Medical (modest). The remaining authors have no disclosures to report. Dr Neeland is supported by grant K23 DK106520 from the National Institutes of Health (NIH) and by the Dedman Family Scholarship in Clinical Care from the University of Texas Southwestern. MESA (Multi-Ethnic Study of Atherosclerosis) was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute (NHLBI); and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences. Dr Allison was supported by funding for MESA Abdominal Body Composition Ancillary study from the NHLBI (R01-HL088451). Dr Karaman acknowledges support from the European Union PhenoMeNal Project (Horizon 2020, 654241). The Development of Combinatorial Biomarkers for Subclinical Atherosclerosis project was supported by a grant from the European Union Seventh Framework Programme (305422). The NEO (Netherlands Epidemiology in Obesity) study is supported by the participating departments, the division, and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area “Vascular and Regenerative Medicine.” We acknowledge support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). Dr Mook-Kanamori is supported by the Dutch Science Organization (ZonMW-VENI Grant 916.14.023). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Keywords

  • adipose tissue
  • cohort
  • metabolite
  • metabolomics
  • obesity
  • visceral adipose tissue

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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