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Pediatrics

Minor diplotypes of FMO3 might protect children and adolescents from obesity and insulin resistance

International Journal of Obesity volume 42, pages 1243–1248 (2018)Cite this article

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Abstract

In order to assess whether flavin-containing monooxygenase-3 (FMO3) might be involved in early cardiovascular risk, we assessed adiposity and traditional metabolic variables in children/adolescents grouped according to their genotypes in two FMO3 exonic polymorphisms, rs2266782 (E158K) and rs2266780 (E308G), which are in linkage disequilibrium and have been associated with decreased FMO3 activity. Among 776 children/adolescents (10.8 ± 2.2 years) recruited from the general population (452) and from our obesity outpatient clinic (324), the 68 carrying either the 158K–308G/158K–308E or the 158K–308G/158K–308G diplotype had lower mean z-BMI and prevalence of obesity compared to their 708 peers carrying any of the other diplotypes (0.39 vs 0.80, p = 0.01; OR = 0.39[0.17–0.87], p = 0.018, respectively), and to the sub-sample of 303 children carrying the major diplotype (158E–308E/158E–308E) (0.39 vs 0.87, p = 0.008; OR = 0.35[0.16–0.81], p = 0.014, respectively). They also had lower z-BMI-adjusted lnHOMA-IR compared to all the other children (0.75 vs 0.97, p = 0.001) and those carrying the major diplotype, (0.75 vs 0.98, p = 0.03), as well as lower z-BMI-adjusted iln-triglycerides compared to all the other children (3.98 vs 4.17, p = 0.037). These associations provide the first evidence that FMO3 may be involved in early body weight, insulin sensitivity, and lipid regulation in humans.

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References

  1. Al-Saeed AH, Constantino MI, Molyneaux L, D’Souza M, Limacher-Gisler F, Luo C, et al. An inverse relationship between age of type 2 diabetes onset and complication risk and mortality: the impact of youth-onset type 2 diabetes. Diabetes Care. 2016;39:823–9.

    Article  PubMed  CAS  Google Scholar 

  2. Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med. 2010;362:485–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Park MH, Falconer C, Viner RM, Kinra S. The impact of childhood obesity on morbidity and mortality in adulthood: a systematic review. Obes Rev. 2012;13:985–1000.

    Article  PubMed  CAS  Google Scholar 

  4. Morrison JA, Glueck CJ, Woo JG, Wang P. Risk factors for cardiovascular disease and type 2 diabetes retained from childhood to adulthood predict adult outcomes: the Princeton LRC follow-up study. Int J Pediatr Endocrinol. 2012;2012:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholin and cardiovascular risk. N Engl J Med. 2013;368:1575–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Tang WH, Wang Z, Shrestha K, Borowski AG, Wu Y, Troughton RW, et al. Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail. 2015;21:91–96.

    Article  PubMed  CAS  Google Scholar 

  9. Miao J, Ling AV, Manthena PV, Gearing ME, Graham MJ, Crooke RM, et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun. 2015;6:6498.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Warrier M, Shih DM, Burrows AC, Ferguson D, Gromovsky AD, Brown AL, et al. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 2015;10:1–13.

    Article  CAS  Google Scholar 

  11. Cho CE, Caudill MA. Trimethylamine-N-Oxide: friend, foe or simply caught in the cross-fire? Trends Endocrinol Metab. 2017;28:121–30.

    Article  PubMed  CAS  Google Scholar 

  12. Schugar RC, Shih DM, Warrier M, Helsley RN, Burrows A, Ferguson D, et al. The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of white adipose tissue. Cell Rep. 2017;19:2451–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Takemoto K, Deckelbaum RJ, Saito I, Litikmaskul S, Morandi A, Pinelli L, et al. Adiponectin/resistin levels and insulin resistance in children: a four country comparison study. Int J Pediatr Endocrinol. 2015;2015:2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest. 2006;29:581–93.

    Article  PubMed  CAS  Google Scholar 

  15. D’Angelo R, Esposito T, Calabrò M, Rinaldi C, Robledo R, Varriale B, et al. FMO3 allelic variants in Sicilian and Sardinian populations: trimethylaminuria and absence of fish-like body odor. Gene. 2013;515:410–15.

    Article  PubMed  CAS  Google Scholar 

  16. Teitelbaum AM, Murphy SE, Akk G, Baker TB, Germann A, von Weymarn LB, et al. Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain. Pharm J. 2017;18:136–43. Epub ahead of print.

    Google Scholar 

  17. Söderberg MM, Haslemo T, Molden E, Dahl ML. Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients. Pharm J. 2013;13:544–50.

    Google Scholar 

  18. Tang YJ, Hu K, Huang WH, Wang CZ, Liu Z, Chen Y, et al. Effects of FMO3 Polymorphisms on pharmacokinetics of sulindac in chinese healthy male volunteers. Biomed Res Int. 2017;2017:4189678.

    PubMed  PubMed Central  Google Scholar 

  19. Lambert DM, Mamer OA, Akerman BR, Choinière L, Gaudet T, Hamet P, et al. In vivo variability of tma oxidation is partially mediated by polymorphisms of the FMO3 Gene. Mol Genet Metab. 2001;73:224–9.

    Article  PubMed  CAS  Google Scholar 

  20. Sachse C, Ruschen S, Dettling M, Schley J, Bauer S, Oerlinghausen Müller, et al. Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism. Clin Pharmacol Ther. 1999;66:431–8.

    Article  PubMed  CAS  Google Scholar 

  21. Hao DC, Sun J, Furnes B, Schlenk D, Hou Z-F, Zhang Y-P, et al. Haplotype frequency distribution and linkage disequilibrium analysis of single nucleotide polymorphisms at the human FMO3 gene locus. Biochem Genet. 2006;44:391–407.

    PubMed  CAS  Google Scholar 

  22. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.

    Google Scholar 

  23. Shan Z, Sun T, Huang H, Chen S, Chen L, Luo C, et al. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Am J Clin Nutr. 2017;106:888–94.

    PubMed  CAS  Google Scholar 

  24. Seldin MM, Meng Y, Qi H, Zhu SL, Wang W, Hazen Z, et al. Trimethylamine N-Oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc. 2016;5:e002767.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are sincerely indebted to the children and adolescents who participated in the study and their families. We wish to thank the dedicated staff of the Pediatric Diabetes and Metabolic Disorders Unit of the University Hospital in Verona for their support during the clinical study.

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Authors and Affiliations

  1. Pediatric Diabetes and Metabolic Disorders Unit, University Hospital of Verona, Verona, Italy

    Anita Morandi, Chiara Zusi, Massimiliano Corradi, Francesca Olivieri, Claudia Piona, Elena Fornari & Claudio Maffeis

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  1. Anita Morandi
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  2. Chiara Zusi
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Correspondence to Claudio Maffeis.

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Morandi, A., Zusi, C., Corradi, M. et al. Minor diplotypes of FMO3 might protect children and adolescents from obesity and insulin resistance. Int J Obes 42, 1243–1248 (2018). https://doi.org/10.1038/s41366-018-0100-7

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