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Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change
Open accessAbstract
BACKGROUND: Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood. METHODS AND FINDINGS: We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92). CONCLUSIONS: Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
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Metadata
- Authors
- Würtz, P., Wang, Q., Kangas, A. J., Richmond, R. C., Skarp, J., Tiainen, M., Tynkkynen, T., Soininen, P., Havulinna, A. S., Kaakinen, M., Viikari, J. S., Savolainen, M. J., Kähönen, M., Lehtimäki, T., Männistö, S., Blankenberg, S., Zeller, T., Laitinen, J., Pouta, A., Mäntyselkä, P., Vanhala, M., Elliott, P., Pietiläinen, K. H., Ripatti, S., Salomaa, V., Raitakari, O. T., Järvelin, M.-R., Smith, G. D., & Ala-Korpela, M.
- Affiliations
- University of Helsinki (FI)
- University of Eastern Finland (FI)
- University of Bristol (GB)
- University of Oulu (FI)
- University of Turku (FI)
- Oulu University Hospital (FI)
- Tampere University Hospital (FI)
- Fimlab (Finland) (FI)
- Finnish Institute for Health and Welfare (FI)
- Universität Hamburg (DE)
- Finnish Institute of Occupational Health (FI)
- MRC Centre for Environment and Health (GB)
- Corresponding author
- Würtz, Peter
- ORCID
- Würtz, Peter
- Wang, Qin
- Kangas, Antti J.
- Richmond, Rebecca C.
- Tiainen, Mika
- Tynkkynen, Tuulia
- Havulinna, Aki S.
- Kaakinen, Marika
- Viikari, Jorma S.
- Savolainen, Markku J.
- Kähönen, Mika
- Lehtimäki, Terho
- Männistö, Satu
- Blankenberg, Stefan
- Zeller, Tanja
- Laitinen, Jaana
- Mäntyselkä, Pekka
- Vanhala, Mauno
- Elliott, Paul
- Pietiläinen, Kirsi H.
- Ripatti, Samuli
- Salomaa, Veikko
- Raitakari, Olli T.
- Järvelin, Marjo-Riitta
- Smith, George Davey
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-12-09
- Volume
- 11
- Issue
- 12
- Pages
- e1001765
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC4260795
- OpenAlex
- W2010768303
- Cited by
- 280
- References
- 47
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 13 · 2023: 22 · 2022: 23 · 2021: 29 · 2020: 36 · 2019: 25 · 2018: 31 · 2017: 34 · 2016: 33 · 2015: 13
- FWCI
- 20.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Pfizer
- Foundation for Cardiovascular Research
- National Institute for Health and Care Research (NF-SI-0611-10136)
- Imperial College London
- European Commission (277849, 278913)
- Kela
- Academy of Finland (#266286, 124,282, 134309, 137870, 121584, 136895, 129378, 129429, 129269, 117,797, 126,925, 250422, 129418, 41071, 120315, 263836, 139635, 104781)
- Suomen Kulttuurirahasto
- Juho Vainion Säätiö (266286)
- Novo Nordisk
- Emil Aaltosen Säätiö
- Turun Yliopisto
- Sydäntutkimussäätiö (121584, 124282, 266286, 134309, 126925, 129378, 41071)
- Oulun Yliopisto (137870, 129429, 129269)
- Paavo Nurmen Säätiö
- Novo Nordisk Fonden (NNF13OC0005747, #NNF10OC1013354)
- Diabetestutkimussäätiö (266286)
- National Institutes of Health (6r01hl087679-03, 5rl1mh083268-05)
- Abbott Diagnostics
- Medical Research Council (MR/L01341X/1)
- Jenny ja Antti Wihurin Rahasto
- Biocenter, University of Oulu
- National Heart, Lung, and Blood Institute (5R01HL087679, R01 HL087679)
- National Institute of Mental Health (RL1-MH083268, 1RL1MH083268)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- adiposity, body mass index, circulating metabolites, cardiometabolic risk, Mendelian randomization, weight change, adolescents and young adults, lipoprotein subclasses, branched-chain amino acids, aromatic amino acids, glycoprotein acetyls, sex differences, metabolic signatures, cardiometabolic disease
- MeSH terms
- Adult, Body Weight, Cross-Sectional Studies, Female, Humans, Male, Body Mass Index, Adiposity, Young Adult, Mendelian Randomization Analysis
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