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Association of plasma kynurenine pathway metabolite concentrations with metabolic health risk in prepubertal Asian children

International Journal of Obesity volume 46, pages 1128–1137 (2022)Cite this article

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Abstract

Background

The tryptophan-kynurenine (KYN) pathway is linked to obesity-related systemic inflammation and metabolic health. The pathway generates multiple metabolites, with little available data on their relationships to early markers of increased metabolic disease risk in children. The aim of this study was to examine the association of multiple KYN pathway metabolites with metabolic risk markers in prepubertal Asian children.

Methods

Fasting plasma concentrations of KYN pathway metabolites were measured using liquid chromatography-tandem mass spectrometry in 8-year-old children (n = 552) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective mother-offspring cohort study. The child’s weight and height were used to ascertain overweight and obesity using local body mass index (BMI)-for-age percentile charts. Body fat percentage was measured by quantitative magnetic resonance. Abdominal circumference, systolic and diastolic blood pressure, homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, and HDL-cholesterol were used for the calculation of Metabolic syndrome scores (MetS). Serum triglyceride, BMI, gamma-glutamyl transferase (GGT), and abdominal circumference were used in the calculation of the Fatty liver index (FLI). Associations were examined using multivariable regression analyses.

Results

In overweight or obese children (n = 93; 16.9% of the cohort), all KYN pathway metabolites were significantly increased, relative to normal weight children. KYN, kynurenic acid (KA), xanthurenic acid (XA), hydroxyanthranilic acid (HAA) and quinolinic acid (QA) all showed significant positive associations with body fat percentage (B(95% CI) = 0.32 (0.22,0.42) for QA), HOMA-IR (B(95% CI) = 0.25 (0.16,0.34) for QA), and systolic blood pressure (B(95% CI) = 0.14(0.06,0.22) for QA). All KYN metabolites except 3-hydroxykynurenine (HK) significantly correlated with MetS (B (95% CI) = 0.29 (0.21,0.37) for QA), and FLI (B (95% CI) = 0.30 (0.21,0.39) for QA).

Conclusions

Higher plasma concentrations of KYN pathway metabolites are associated with obesity and with increased risk for metabolic syndrome and fatty liver in prepubertal Asian children.

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Fig. 1: Simplified schematic of the KYN pathway.
Fig. 2: Fold change of KYN metabolites by BMI categories.
Fig. 3: Association of KYN metabolites with metabolic risk factors.
Fig. 4: Association of KYN metabolites with metabolic syndrome score and fatty liver index.

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Acknowledgements

This study group includes: Airu Chia, Allan Sheppard, Amutha Chinnadurai, Anna Magdalena Fogel, Anne Eng Neo Goh, Anne Hin Yee Chu, Anne Rifkin-Graboi, Anqi Qiu, Arijit Biswas, Bee Wah Lee, Birit Froukje Philipp Broekman, Bobby Kyungbeom Cheon, Boon Long Quah, Candida Vaz, Chai Kiat Chng, Cheryl Shufen Ngo, Choon Looi Bong, Christiani Jeyakumar Henry, Ciaran Gerard Forde, Claudia Chi, Daniel Yam Thiam Goh, Dawn Xin Ping Koh, Desiree Y. Phua, Doris Ngiuk Lan Loh, E Shyong Tai, Elaine Kwang Hsia Tham, Elaine Phaik Ling Quah, Elizabeth Huiwen Tham, Evelyn Chung Ning Law, Evelyn Xiu Ling Loo, FKPY, Faidon Magkos, Falk Müller-Riemenschneider, George Seow Heong Yeo, Hannah Ee Juen Yong, Helen Yu Chen, Heng Hao Tan, Hong Pan, Hugo P S van Bever, Hui Min Tan, Iliana Magiati, Inez Bik Yun Wong, Ives Yubin Lim, Ivy Yee-Man Lau, Izzuddin Bin Mohd Aris, Jeannie Tay, Jeevesh Kapur, Jenny L. Richmond, Jerry Kok Yen Chan, Jia Xu, Joanna Dawn Holbrook, Joanne Su-Yin Yoong, Joao Nuno Andrade Requicha Ferreira, JGE, Jonathan Tze Liang Choo, Jonathan Y. Bernard, Jonathan Yinhao Huang, Joshua J. Gooley, Jun Shi Lai, KMLT, KMG, Kenneth Yung Chiang Kwek, Keri McCrickerd, KHT, NK, Krishnamoorthy Naiduvaje, Kuan Jin Lee, Leher Singh, Li Chen, Lieng Hsi Ling, Lin Lin Su, Ling-Wei Chen, Lourdes Mary Daniel, Lynette Pei-Chi Shek, Marielle V. Fortier, Mark Hanson, MFFC, Mary Rauff, Mei Chien Chua, Melvin Khee-Shing Leow, Michael J. Meaney, Michelle Zhi Ling Kee, Min Gong, MTT, Navin Michael, Neerja Karnani, Ngee Lek, Oon Hoe Teoh, P. C. Wong, Paulin Tay Straughan, PDG, Pratibha Keshav Agarwal, Priti Mishra, Queenie Ling Jun Li, Rob Martinus van Dam, Salome A. Rebello, Sambasivam Sendhil Velan, Seang Mei Saw, See Ling Loy, Seng Bin Ang, Shang Chee Chong, Sharon Ng, Shiao-Yng Chan, Shirong Cai, Shu-E Soh, Sok Bee Lim, Stella Tsotsi, Stephen Chin-Ying Hsu, Sue-Anne Ee Shiow Toh, Suresh Anand Sadananthan, Swee Chye Quek, Varsha Gupta, Victor Samuel Rajadurai, Walter Stunkel, Wayne Cutfield, Wee Meng Han, Wei Wei Pang, Wen Lun Yuan, Yanan Zhu, YSC, Yin Bun Cheung, Yiong Huak Chan, YSL.

Author contributions

KMT was responsible for designing the study, analyzing data, interpreting results, and writing the manuscript. MTT contributed to designing the study, extracting and analyzing data, interpreting results, and writing the manuscript. NK contributed to analyzing data. FY, KMG, YSL, KHT, PDG, YSC, and MFFC contributed to data collection. KMG, YSL, MFFC, and JGE provided feedback on the manuscript. DCS was responsible for designing the study, interpreting results, and writing the manuscript.

Funding

The study is supported by the National Research Foundation (NRF) under the Open Fund-Large Collaborative Grant (OF-LCG; MOH-000504) administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC) and the Agency for Science, Technology and Research (A*STAR). In RIE2025, GUSTO is supported by funding from the NRF’s Human Health and Potential (HHP) Domain, under the Human Potential Programme

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  1. These authors contributed equally: Karen Mei-Ling Tan, Mya-Thway Tint.

Authors and Affiliations

  1. Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Karen Mei-Ling Tan, Mya-Thway Tint, Narasimhan Kothandaraman, Yung Seng Lee, Peter D. Gluckman, Yap-Seng Chong, Mary F. F. Chong, Johan G. Eriksson & David Cameron-Smith

  2. Department of Laboratory Medicine, National University Hospital, Singapore, Singapore

    Karen Mei-Ling Tan

  3. Human Potential Translational Research Programme, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore

    Mya-Thway Tint & Johan G. Eriksson

  4. Duke-National University of Singapore (NUS) Medical School, Singapore, Singapore

    Fabian Yap & Kok Hian Tan

  5. Department of Pediatric Endocrinology, KK Women’s and Children’s Hospital, Singapore, Singapore

    Fabian Yap

  6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Fabian Yap

  7. MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

    Keith M. Godfrey

  8. NIHR Southampton Biomedical Research Centre, University of Southampton and University of Southampton Hospital, Southampton, UK

    Keith M. Godfrey

  9. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Yung Seng Lee

  10. Khoo Teck Puat – National University Children’s Medical Institute (KTPCMI), National University Health System, Singapore, Singapore

    Yung Seng Lee

  11. Perinatal Audit and Epidemiology, Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore

    Kok Hian Tan

  12. Liggins Institute, University of Auckland, Auckland, New Zealand

    Peter D. Gluckman

  13. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore, Singapore

    Yap-Seng Chong & Johan G. Eriksson

  14. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore

    Mary F. F. Chong

  15. Folkhälsan Research Center, Helsinki, Finland

    Johan G. Eriksson

  16. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

    Johan G. Eriksson

  17. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    David Cameron-Smith

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Competing interests

YSC, PDG, and KMG are part of an academic consortium that has received research funding from companies selling nutritional products. KMG and DCS have received reimbursement for speaking at conferences sponsored by companies selling nutritional products. KMG is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515-10042) and NIHR Southampton Biomedical Research Centre (IS-BRC-1215-20004)), the European Union (Erasmus+ Programme ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP) and the British Heart Foundation (RG/15/17/3174, SP/F/21/150013). All other authors declare no financial relationships with any organizations that might have an interest in the submitted work, and no other relationships or activities that could appear to have influenced the submitted work.

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Tan, K.ML., Tint, MT., Kothandaraman, N. et al. Association of plasma kynurenine pathway metabolite concentrations with metabolic health risk in prepubertal Asian children. Int J Obes 46, 1128–1137 (2022). https://doi.org/10.1038/s41366-022-01085-4

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