Background: Molecular mechanisms underlying the beneficial effects of long-term lifestyle interventions on cardiometabolic health during childhood and adolescence remain largely unknown. Such information would provide valuable insights into the prevention of cardiometabolic diseases since childhood. We therefore studied for the first time the effects of a long-term diet and physical activity (PA) intervention on serum metabolites in a general population of children. Methods: We carried out an 8-year, nonrandomized, controlled trial in a population sample of 490 prepubertal children (257 girls, 233 boys) aged 6-9 years followed up until adolescence. We allocated the children to a combined diet and PA intervention group and a control group. We performed a non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis of fasting serum samples at baseline, two years, and eight years. We analyzed the intervention effects on serum metabolites using linear mixed-effects models adjusting for sex and age. Results: The intervention had effects on 80 serum metabolites over two years, 17 of these metabolites being affected by the interevention until eight years. The intervention had effects on several fatty amides (such as palmitic amide, linoleamide, oleamide, elaidamide, capsiamide, myristamide, palmitoleamide, docosanamide, and erucamide), unsaturated fatty acids (such as 12-hydroxyheptadecatrienoic acid, hydroxyeicosatetraenoic acid, hydroxyoxohexadecanoic acid, and oxotetradecenoic acid), and acylcarnitines (such as octanoyl-L-carnitine, decatrienoylcarnitine, and valerylcarnitine) as well as many phospholipids and sterols over two years. Moreover, the intervention affected several gut-microbiota-derived metabolites (such as hydroxyferulic acid, hippuric acid, indolepropionic acid, pyrocatechol sulfate, 3-carboxy-4-methyl-5-pentyl-2-furanpropanoic acid, p-cresol sulfate, indolelactic acid, and 3,4-dimethyl-5-pentyl-2-furanpropanoic acid), amino acids (such as methoxybenzenepropanoic acid, glutamic acid, taurine, and hydroxyisoleucine), and purine metabolites (such as guanosine, inosine, xanthine, and hypoxanthine) over two years. Conclusions: The diet and PA intervention had long-term effects on numerous serum metabolites that could influence cardiometabolic health since childhood. The intervention effects were most pronounced on serum fatty amides, but the intervention also affected other potentially important serum lipids, including fatty acids, acylcarnitines, phospholipids, and sterols, as well as serum gut-microbiota-derived metabolites, amino acids, and purine metabolites. These metabolites could be molecular mechanisms underlying the beneficial effects of long-term lifestyle interventions on cardiometabolic health since childhood.

KH, VMK, and AK are affiliated with Afekta Technologies Ltd Afekta Technologies Ltd. Metabolomics service company. Other authors of this article declare no competing interests.

ClinicalTrials.gov NCT01803776

https://www.panicstudy.fi/

The PANIC study has been supported financially by grants from the Academy of Finland, the Ministry of Education and Culture of Finland, the Ministry of Social Affairs and Health of Finland, the Research Committee of the Kuopio University Hospital Catchment Area (State Research Funding), Finnish Innovation Fund Sitra, Social Insurance Institution of Finland, Finnish Cultural Foundation, Foundation for Pediatric Research, Diabetes Research Foundation in Finland, Finnish Foundation for Cardiovascular Research, Juho Vainio Foundation, Paavo Nurmi Foundation, Yrjo Jahnsson Foundation, and the city of Kuopio. Moreover, the current work was supported by Horizon 2020 research and innovation programme of European Union (Grant 874739 for LongITools project) to MK, TAL, and KH. The funding bodies have no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Ethics approval and consent to participate: The Research Ethics Committee of the Hospital District of Northern Savo approved the study protocol in 2006 and 2015 (Statements 69/2006 and 422/2015). The caregivers gave their written informed consent, and the children provided their assent to participation. Moreover, the caregivers and adolescents gave their written informed consent before 8-year examinations.

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