Associations of the BDNF Val66Met Polymorphism With Body Composition, Cardiometabolic Risk Factors, and Energy Intake in Youth With Obesity: Findings From the HEARTY Study

Gary S Goldfield, Jeremy Walsh, Ronald J Sigal, Glen P Kenny, Stasia Hadjiyannakis, Michael De Lisio, Mathew Ngu, Denis Prud'homme, Angela S Alberga, Steve Doucette, Diana B Goldfield, Jameason D Cameron, Gary S Goldfield, Jeremy Walsh, Ronald J Sigal, Glen P Kenny, Stasia Hadjiyannakis, Michael De Lisio, Mathew Ngu, Denis Prud'homme, Angela S Alberga, Steve Doucette, Diana B Goldfield, Jameason D Cameron

Abstract

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is functionally related to BDNF, and is associated with obesity and metabolic complications in adults, but limited research exists among adolescents. This study comparatively examined carriers and non-carriers of the BDNF Val66Met polymorphism on body composition, energy intake, and cardiometabolic profile among adolescents with obesity. The sample consisted of 187 adolescents with obesity; 99 were carriers of the homozygous Val (G/G) alleles and 88 were carriers of the Val/Met (G/A) or Met (A/A) alleles. Cardiometabolic profile and DNA were quantified from fasted blood samples. Body composition was assessed by magnetic resonance imaging (MRI). Compared to carriers of the homozygous Val (G/G) allele, carriers of the Val/Met (G/A) or Met/Met (A/A) variants exhibited significantly higher protein (p = 0.01) and fat (p = 0.05) intake, C-Reactive protein (p = 0.05), and a trend toward higher overall energy intake (p = 0.07), fat-free mass (p = 0.07), and lower HDL-C (p = 0.07) Results showed for the first time that among youth with obesity, carriers of the Val66Met BDNF Met-alleles exhibited significantly higher C-reactive protein and energy intake in the form of fat and protein compared to Val-allele carriers, thereby providing support for the possible role of BDNF in appetite, weight, and metabolic regulation during adolescence. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT00195858" title="See in ClinicalTrials.gov">NCT00195858.

Keywords: BDNF; Val66Met; adolescents; cardiometabolic risk; energy intake; gene; obesity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Goldfield, Walsh, Sigal, Kenny, Hadjiyannakis, De Lisio, Ngu, Prud’homme, Alberga, Doucette, Goldfield and Cameron.

References

    1. Alberga A. S., Goldfield G. S., Kenny G. P., Hadjiyannakis S., Phillips P., Prud’Homme D., et al. (2012). Healthy eating, aerobic and resistance training in youth (HEARTY): study rationale, design and methods. Contemp. Clin. Trials 33 839–847.
    1. Alberga A. S., Prud’Homme D., Kenny G. P., Goldfield G. S., Hadjiyannakis S., Gougeon R., et al. (2015). Effects of aerobic and resistance training on abdominal fat, apolipoproteins and high-sensitivity C-reactive protein in adolescents with obesity: the HEARTY randomized clinical trial. Int. J. Obes. 39 1494–1500.
    1. Anastasia A., Deinhardt K., Chao M. V., Will N. E., Irmady K., Lee F. S., et al. (2013). Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat. Commun. 4:2490. 10.1038/NCOMMS3490
    1. Arija V., Ferrer-Barcala M., Aranda N., Canals J. (2010). BDNF Val66Met polymorphism, energy intake and BMI: a follow-up study in schoolchildren at risk of eating disorders. BMC Public Health 10:363. 10.1186/1471-2458-10-363
    1. Bariohay B., Lebrun B., Moyse E., Jean A. (2005). Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology 146 5612–5620. 10.1210/en.2005-0419
    1. Cameron J. D., Sigal R. J., Kenny G. P., Alberga A. S., Prud’Homme D., Phillips P., et al. (2016). Body composition and energy intake - skeletal muscle mass is the strongest predictor of food intake in obese adolescents: the HEARTY trial. Appl. Physiol. Nutr. Metab. 41 611–617.
    1. Carlino D., Leone E., Di Cola F., Baj G., Marin R., Dinelli G., et al. (2011). Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia. J. Psychiatr. Res. 45 273–279. 10.1016/j.jpsychires.2010.06.012
    1. Cohen J. (1977). Statistical Power Analysis for the Behavioral Sciences. New York, NY: Lawrence Erlbaum.
    1. Di Cesare M., Sorić M., Bovet P., Miranda J. J., Bhutta Z., Stevens G. A., et al. (2019). The epidemiological burden of obesity in childhood: a worldwide epidemic requiring urgent action. BMC Med. 17:212. 10.1186/s12916-019-1449-8
    1. Donovan M. J., Miranda R. C., Kraemer R., McCaffrey T. A., Tessarollo L., Mahadeo D., et al. (1995). Neurotrophin and neurotrophin receptors in vascular smooth muscle cells: regulation of expression in response to injury. Am. J. Pathol. 147 309–324.
    1. Egan M., Kojima M., Callicott J., Goldberg T. E., Kolachana B. S., Bertolino A., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112 257–269.
    1. Emanueli C., Meloni M., Hasan W., Habecker B. A. (2014). “The biology of neurotrophins: cardiovascular function,” in Neurotrophic Factors, eds Lewin G., Carter B. (Berlin: Springer; ), 309–328. 10.1007/978-3-642-45106-5
    1. Ethel I., Ethel D. (2007). Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J. Neurosci. Res. 85 2813–2823.
    1. Farooqi I. S., O’Rahilly S. (2007). Genetic factors in human obesity. Obes. Rev. 8 37–40. 10.1111/j.1467-789X.2007.00315.x
    1. Friedel S., Fontenla Horro F., Wermter A. K., Geller F., Dempfle A., Reichwald K., et al. (2005). Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 132B 96–99. 10.1002/ajmg.b.30090
    1. Friedewald W. T., Levy R. I., Fredrickson D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18 499–502.
    1. Goldfield G. S., Kenny G. P., Alberga A. S., Prud’Homme D., Hadjiyannakis S., Gougeon R., et al. (2015). Effects of aerobic training, resistance training, or both on psychological health in adolescents with obesity: the HEARTY randomized controlled trial. J. Consult. Clin. Psychol. 83 1123–1135.
    1. Goldfield G. S., Kenny G. P., Alberga A. S., Tulloch H. E., Doucette S., Cameron J. D., et al. (2017). Effects of aerobic or resistance training or both on health-related quality of life in youth with obesity: the HEARTY Trial. Appl. Physiol. Nutr. Metab. 42 361–370.
    1. Gratacòs M., González J. R., Mercader J. M., de Cid R., Urretavizcaya M., Estivill X. (2007). Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol. Psychiatry 61 911–922. 10.1016/j.biopsych.2006.08.025
    1. Gray J., Yeo G. S. H., Cox J. J., Morton J., Adlam A. L. R., Keogh J. M., et al. (2006). Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes Metab. Res. Rev. 55 3366–3371. 10.2337/db06-0550
    1. Guo J., Ji Y., Ding Y., Jiang W., Sun Y., Lu B., et al. (2016). BDNF pro-peptide regulates dendritic spines via caspase-3. Cell Death Dis. 7:e2264. 10.1038/cddis.2016.166
    1. Jiang H., Wang R., Liu Y., Zhang Y., Chen Z. Y. (2009). BDNF Val66Met polymorphism is associated with unstable angina. Clin. Chim. Acta 400 3–7. 10.1016/j.cca.2008.10.017
    1. Jiang R., Babyak M. A., Brummett B. H., Hauser E. R., Shah S. H., Becker R. C., et al. (2017). Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort. Am. Heart J. 190 40–45. 10.1016/j.ahj.2017.05.002
    1. Kalenda A., Landgraf K., Löffler D., Kovacs P., Kiess W., Körner A. (2018). The BDNF Val66Met polymorphism is associated with lower BMI, lower postprandial glucose levels and elevated carbohydrate intake in children and adolescents. Pediatr. Obes. 13 159–167. 10.1111/ijpo.12238
    1. Kermani P., Raffi D., Jin D., Whitlock P., Schaffer W., Chiang A., et al. (2005). Neurotrophins promote revascularization by local recruitment of. J. Clin. Invest. 115 653–663.
    1. Kernie S. G., Liebl D. J., Parada L. F. (2000). BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19 1290–1300.
    1. Krabbe K. S., Nielsen A. R., Krogh-Madsen R., Plomgaard P., Rasmussen P., Erikstrup C., et al. (2007). Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50 431–438.
    1. László A., Lénárt L., Illésy L., Fekete A., Nemcsik J. (2019). The role of neurotrophins in psychopathology and cardiovascular diseases: psychosomatic connections. J. Neural. Transm. 126 265–278. 10.1007/s00702-019-01973-6
    1. Leatherdale S. T., Harvey A. (2015). Examining communication-and-media-based recreational sedentary behaviors among Canadian youth: Results from the COMPASS study. Prev. Med. 74 74–80.
    1. Lebrun B., Bariohay B., Moyse E., Jean A. (2006). Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview. Auton. Neurosci. 126-127 30–38. 10.1016/j.autneu.2006.02.027
    1. León-Mimila P., Villamil-Ramírez H., Villalobos-Comparán M., Villarreal-Molina T., Romero-Hidalgo S., López-Contreras B., et al. (2013). Contribution of Common Genetic Variants to Obesity and Obesity-Related Traits in Mexican Children and Adults. PLoS One 8:e70640. 10.1371/journal.pone.0070640
    1. Liang J., Matheson B. E., Kaye W. H., Boutelle K. N. (2016). Neurocognitve correlates of obesity and obesity-related behaviors in children and adolescents. Int. J. Obes. 38 494–506.
    1. Lorgis L., Amoureux S., Vergely C., Zeller M., Cottin Y., Rochette L. (2009). Brain-Derived Neurotrophic Factor (BDNF): role of this neurotrophin in cardiovascular physiopathology. Ann. Cardiol. d’Angeiol. 58 99–103. 10.1016/j.ancard.2008.11.001
    1. Marosi K., Mattson M. P. (2014). BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol. Metab. 25 89–98.
    1. Martínez-Ezquerro J. D., Rendón-Macías M. E., Zamora-Mendoza G., Serrano-Meneses J., Rosales-Rodríguez B., Escalante-Bautista D., et al. (2017). Association Between the Brain-derived Neurotrophic Factor Val66Met Polymorphism and Overweight/Obesity in Pediatric Population. Arch. Med. Res. 48 599–608. 10.1016/j.arcmed.2018.02.005
    1. Matthews V. B., Astrom M. B., Chan M. H., Bruce C. R., Krabbe K. S., Prelovsek O., et al. (2009). Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52 1409– 1418.
    1. McNeil J., Lamothe G., Cameron J. D., Riou M.-È., Cadieux S., Lafrenière J., et al. (2017). Investigating predictors of eating: Is resting metabolic rate really the strongest proxy of energy intake? Am. J. Clin. Nutr. 106 1206–1212. 10.3945/ajcn.117.153718
    1. Mitra S., Fernandez-Del-Valle M., Hill J. E. (2017). The role of MRI in understanding the underlying mechanisms in obesity associated diseases. Biochim. Biophys. Acta 1863 1115–1131. 10.1016/j.bbadis.2016.09.008
    1. Mizui T., Ishikawa Y., Kumanogoh H., Lume M., Matsumoto T., Hara T., et al. (2016). BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc. Natl Acad. Sci. U.S.A. 112 E3067–E3074. 10.1073/pnas.1422336112
    1. Peng J. H., Liu C. W., Pan S. L., Wu H. Y., Liang Q. H., Gan R. J., et al. (2017). Potential unfavorable impacts of BDNF Val66Met polymorphisms on metabolic risks in average population in a longevous area. BMC Geriatr. 17:4. 10.1186/s12877-016-0393-0
    1. Pius-Sadowska E., Machaliński B. (2017). BDNF – A key player in cardiovascular system. J. Mol. Cell. Cardiol. 110 54–60. 10.1016/j.yjmcc.2017.07.007
    1. Poslusna K., Ruprich J., De Vries J. H. M., Jakubikova M., Van’T Veer P. (2009). Misreporting of energy and micronutrient intake estimated by food records and 24hour recalls, control and adjustment methods in practice. Br. J. Nutr. 101(Suppl. 2), S73–S85. 10.1017/S0007114509990602
    1. Prigent-Tessier A., Quirie A., Maguin-Gate K., Szostak J., Mossiat C., Nappey M., et al. (2013). Physical training and hypertension have opposite effects on endothelial brain-derived neurotrophic factor expression. Cardiovasc. Res. 100 374–382. 10.1093/cvr/cvt219
    1. Rana S., Sultana A., Bhatti A. A. (2019). Association of BDNF rs6265 and MC4R rs17782313 with metabolic syndrome in Pakistanis. J. Biosci. 44 95. 10.1007/s12038-019-9915-1
    1. Rios M. (2013). BDNF and the central control of feeding: Accidental bystander or essential player? Trends Neurosci. 36 83–90. 10.1016/j.tins.2012.12.009
    1. Ross R., Leger L., Morris D., de Guise J., Guardo R. (1992). Quantification of adipose tissue by MRI: relationship with anthropometric variables. J. Appl. Physiol. 72 787–795.
    1. Sheikh H. I., Hayden E. P., Kryski K. R., Smith H. J., Singh S. M. (2010). Genotyping the BDNF rs6265 (val66met) polymorphism by one-step amplified refractory mutation system PCR. Psychiatr. Genet. 20 109–112. 10.1097/YPG.0b013e32833a2038
    1. Shen T., You Y., Joseph C., Mirzaei M., Klistorner A., Graham S. L., et al. (2018). BDNF polymorphism: a review of its diagnostic and clinical relevance in neurodegenerative disorders. Aging Dis. 9 523–536. 10.14336/AD.2017.0717
    1. Shugart Y. Y., Chen L., Day I. N. M., Lewis S. J., Timpson N. J., Yuan W., et al. (2009). Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI. Eur. J. Hum. Genet. 17 1050–1055. 10.1038/ejhg.2008.272
    1. Sigal R. J., Alberga A. S., Goldfield G. S., Prud’homme D., Hadjiyannakis S., Gougeon R., et al. (2014). Effects of aerobic training, resitance training, or both on percentage body fat and cardiometabolic risk markers in obese adolescents: the healthy eating aerobic and resistance training in youth randomized clinical trial. JAMA Pediatr. 168 1006–1014.
    1. Skledar M., Nikolac M., Dodig-Curkovic K., Curkovic M., Borovecki F., Pivac N. (2012). Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents. Prog. Neuro Psychopharmacol. Biol. Psychiatry 36 136–140.
    1. Stein S., Winnik S., Matter C. M. (2017). Brain-derived neurotrophic factor Val66Met polymorphism in depression and thrombosis: SIRT1 as a possible mediator. Eur. Heart J. 38 1436–1438. 10.1093/eurheartj/ehv692
    1. Sustar A., Nikolac Perkovic M., Nedic Erjavec G., Svob Strac D., Pivac N. (2016). A protective effect of the BDNF Met/Met genotype in obesity in healthy Caucasian subjects but not in patients with coronary heart disease. Eur. Rev. Med. Pharmacol. Sci. 20 3417–3426.
    1. Tabachnick B. G., Fidell L. S. (2007). Using Multivariate Statistics, 5th Edn. Boston, MA: Allyn and Bacon.
    1. Teng H. K., Teng K. K., Lee R., Wright S., Tevar S., Almeida R. D., et al. (2005). ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25 5455–5463. 10.1523/JNEUROSCI.5123-04.2005
    1. Tsuchida A., Nakagawa T., Itakura Y., Ichihara J., Ogawa W., Kasuga M., et al. (2001). The effects of brain-derived neurotrophic factor on insulin signal transduction in the liver of diabetic mice. Diabetologia 44 555–566. 10.1007/s001250051661
    1. van Holten T. C., Waanders L. F., de Groot P. G., Vissers J., Hoefer I. E., Pasterkamp G., et al. (2013). Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One 8:e62080. 10.1371/journal.pone.0062080
    1. Vidovic V., Maksimovic N., Novakovic I., Damnjanovic T., Jekic B., Vidovic S., et al. (2020). Association of the brain-derived neurotrophic factor Val66Met polymorphism with body mass index, fasting glucose levels and lipid status in adolescents. Balkan J. Med. Sci. 23 77–82.
    1. Voineskos A. N., Lerch J. P., Felsky D., Shaikh S., Rajji T. K., Miranda D., et al. (2011). The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for alzheimer disease. Arch. Gen. Psychiatry 68 198–206. 10.1001/archgenpsychiatry.2010.194
    1. Walsh J. J., D’Angiulli A., Cameron J. D., Sigal R. J., Kenny G. P., Holcik M., et al. (2018). Changes in the Brain-Derived Neurotrophic Factor Are Associated with Improvements in Diabetes Risk Factors after Exercise Training in Adolescents with Obesity: the HEARTY Randomized Controlled Trial. Neural Plast. 2018 7169583. 10.1155/2018/7169583
    1. Wellman N. S., Friedberg B. (2002). Causes and consequences of adult obesity: health, social and economic impacts in the United States. Asia Pac. J. Clin. Nutr. 11 S705–S709. 10.1046/j.1440-6047.11.s8.6.x
    1. World Medical Association (2013). World Medical Association Declaration of Helsinki ethical principles for medical research involving human subjects. JAMA 310, 2191–2194. 10.1001/jama.2013.281053
    1. Wu L., Xi B., Zhang M., Shen Y., Zhao X., Cheng H., et al. (2010). Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in chinese children. Diabetes Metab. Res. Rev. 59 3085–3089. 10.2337/db10-0273
    1. Xi B., Cheng H., Shen Y., Chandak G. R., Zhao X., Hou D., et al. (2013). Study of 11 BMI-Associated Loci Identified in GWAS for associations with central obesity in the Chinese children. PLoS One 8:e56472. 10.1371/journal.pone.0056472
    1. Yamanaka M., Tsuchida A., Nakagawa T., Nonomura T., Ono-Kishino M., Sugaru E., et al. (2007). Brain-derived neurotrophic factor enhances glucose utilization in peripheral tissues of diabetic mice. Diabetes. Obes. Metab. 9 59–64. 10.1111/j.1463-1326.2006.00572.x
    1. Yoshida T., Ishikawa M., Niitsu T., Nakazato M., Watanabe H., Shiraishi T., et al. (2013). Decreased serum levels of mature Brain-Derived Neurotrophic Factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 7:e42676. 10.1371/journal.pone.0042676
    1. Zagrebelsky A., Holz A., Dechant G., Barde Y., Bonhoefer T., Korte M. (2005). The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J. Neurosci. 25 9989–9999.
    1. Zanin J. P., Unsain N., Anastasia A. (2017). Growth factors and hormones pro-peptides: the unexpected adventures of the BDNF prodomain. J. Neurochem. 141 330–340. 10.1111/jnc.13993
    1. Zhao J., Bradfield J. P., Li M., Wang K., Zhang H., Kim C. E., et al. (2009). The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI. Obesity 17 2254–2257. 10.1038/oby.2009.159
    1. Zhao M., Chen L., Yang J., Fang D., Qiu X., Ma J., et al. (2018). BDNF Val66Met polymorphism, life stress and depression: a meta-analysis of gene-environment interaction. J. Affect. Disord. 227 226–235.
    1. Zhao X., Yang Y., Sun B. F., Zhao Y. L., Yang Y. G. (2014). FTO and obesity: mechanisms of association. Curr. Diabetes Rep. 14:486. 10.1007/s11892-014-0486-0

Source: PubMed

3
Abonneren