The influence of С.189G>A P.(Val66Met) polymorphism of the BDNF gene on serum leptin levels in Yakuts


DOI: https://dx.doi.org/10.18565/therapy.2021.9.58-65

Nikanorova A.A., Barashkov N.A., Nakhodkin S.S., Pshennikova V.G., Gotovtsev N.N., Solovyev A.V., Romanov G.P., Kuzmina S.S., Sazonov N.N., Fedorova S.A.

1) Yakutsk Scientific Center for Complex Medical Problems; 2) M.K. Ammosov North-Eastern University, Yakutsk
Abstract. Numerous studies indicate that BDNF may play an important role in energy homeostasis, in the regulation of food intake, and in the peripheral regulation of metabolism.
The aim of the research was to search for the correlation between single nucleotide polymorphism c.189G> A p. (Val66Met) of the BDNF gene and the levels of circulating in blood leptin in Yakut population.
Material and methods. Study sample consisted of 281 persons (186 females and 95 males), the average age of the participants was 19,8±1,5 years. The sample was stratified by sex and subdivided according to body mass index (BMI) into three groups: underweight (n=37), normal weight (n=215), and overweight/obesity (n=29) group.
Results. In the Yakut population, the frequency of the major allele p. (Val66) was 84,9%, the minor allele p. (Met66) – 15,1%. Due to the low frequency of distribution of homozygotes p. [Met66]; [Met66] and heterozygote p. [Val66]; [Met66], in the analysis, these two genotypes were combined into one group p. [Val66]; [Met66] + p. [Met66]; [Met66]. As a result, an association of the genotypes of p. [Val66]; [Met66] + p. [Met66]; [Met66] with decreased serum leptin levels in normal weight females (p=0,01). In males with normal weight, there was a tendency towards a decrease in leptin level in carriers of the genotypes p. [Val66]; [Met66] + p. [Met66]; [Met66] (3,83±0,85 ng/ml) comparatively with homozygotes p. [Val66]; [Val66] (5,58±0,93 ng/ml; p=0,09).
Conclusion. Our results indicate that individuals with p. (Met66) allele probably may have an impaired signaling pathway of leptin through BDNF in the ventromedial hypothalamic nucleus. According to this assumption, carriers of the p. (Met66) allele may have a decreased appetite since their birth time, which leads to a decrease in the amount of consumed foos and an increase in the use of fats in energy metabolism. This, in turn, reduces the accumulation of normal amounts of adipose tissue required for leptin production and is a risk factor for the development of eating disorders associated with anorexia nervosa and bulimia nervosa.
Keywords: Yakuts, p. 189G> A p. (Val66Met), BDNF, leptin, body mass index
Read entire article

Literature


  1. Jones M.E., Schoemaker M.J., Wright L.B. et al. Smoking and risk of breast cancer in the generations study cohort. Breast Cancer Res. 2017; 19(1): 118. doi: 10.1186/s13058-017-0908-4.

  2. Maisonpierre P.C., Le Beau M.M., Espinosa R. et al. Human and rat brain-derived neurotrophic factor and neurotrophin-3: Gene structures, distributions, and chromosomal localizations. Genomics. 1991; 10(3): 558–68. doi: 10.1016/0888-7543(91)90436-I.

  3. Matsuo K., Walss-Bass C., Nery F.G. et al. Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology. 2009; 34(8): 1904–13. doi: 10.1038/npp.2009.23.

  4. Leibrock J., Lottspeich F., Hohn A. et al. Molecular cloning, and expression of brain-derived neurotrophic factor. Nature. 1989; 341(6238): 149–52. doi: 10.1038/341149a0.

  5. Acheson A., Conover J.C., Fandl J.P. et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature .1995; 374(6521): 450–53. doi: 10.1038/374450a0.

  6. Huang L., Wang Z., Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem. 2001; 276(9): 6343–49. doi: 10.1074/jbc.M009795200.

  7. Lommatzsch M., Zingler D., Schuhbaeck K. et al. The impact of age, weight, and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005; 26(1): 115–23. doi: 10.1016/j.neurobiolaging.2004.03.002.

  8. Han H.R., Ryu H.-J., Cha H.S. et al. Genetic variations in the leptin and leptin receptor genes are associated with type 2 diabetes mellitus and metabolic traits in the Korean female population. Clin Genet. 2008; 74(2): 105–15. doi: 10.1111/j.1399-0004.2008.01033.x.

  9. Pedersen B.K., Pedersen M., Krabbe K.S. et al. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol. 2009; 94(12): 1153–60. doi: 10.1113/expphysiol.2009.048561.

  10. Egan M.F., Kojima M., Callicott J.H. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003. 112(2): 257–69. doi: 10.1016/s0092-8674(03)00035-7.

  11. Ribases M., Gratacos M., Fernandez-Aranda F. et al. Association of BDNF with anorexia, bulimia, and age of onset of weight loss in six European populations. Hum Mol Genet. 2004; 13(12): 1205–12. doi: 10.1093/hmg/ddh137.

  12. Gratacos M., Gonzalez J.R., Mercader J.M. et al. 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. 2007; 61(7): 911–22. doi: 10.1016/j.biopsych.2006.08.025.

  13. Ribases M., Gratacos M., Armengol L. et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry. 2003; 8(8): 745–51. doi: 10.1038/sj.mp.4001281.

  14. Koizumi H., Hashimoto K., Itoh K. et al. Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders. Am J Med Genet B Neuropsychiatr Genet. 2004; 127B(1): 125–27. doi: 10.1002/ajmg.b.20153.

  15. De Krom M., Bakker S.C., Hendriks J. et al. Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients. Psychiatr Genet. 2005; 15(2): 81. doi: 10.1097/00041444-200506000-00003.

  16. Friedel S., Horro F.F., Wermter A.K. et al. 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 B Neuropsychiatr Genet. 2005; 132B(1): 96–99. doi: 10.1002/ajmg.b.30090.

  17. Gunstad J., Schofield P., Paul R.H. et al. BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology. 2006; 53(3): 153–56. doi: 10.1159/000093341.

  18. Monteleone P., Zanardini R., Tortorella A. et al. The 196G/A (Val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder. Neurosci Lett. 2006; 406(1–2): 133–37. doi: 10.1016/j.neulet.2006.07.040.

  19. Dardennes R.M., Zizzari P., Tolle V. et al. Family trios’ analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity, and age of onset. Psychoneuroendocrinology. 2007; 32(2): 106–113. doi: 10.1016/j.psyneuen.2006.11.003.

  20. Considine R.V., Kriauciunas A., Ohannesian J.P., Bauer T.L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334(5): 292–95. doi: 10.1056/NEJM199602013340503.

  21. Zhang Y., Chua S. Leptin function and regulation. In Comprehensive Physiology; Terjung, R. Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA. 2017; 351–69. ISBN: 978-0-470-65071-4.

  22. Elmquist J.K., Elias C.F., Saper C.B. From lesions to leptin: Hypothalamic control of food intake and body weight. Neuron. 1999; 22(2): 221–32. doi: 10.1016/s0896-6273(00)81084-3.

  23. Baicy K., London E.D., Monterosso J. et al. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A. 2007; 104(46): 18276–79. doi: 10.1073/pnas.0706481104.

  24. Garfield A.S., Patterson C., Skora S. et al. Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology. 2012; 153(10): 4600–07. doi: 10.1210/en.2012-1282.

  25. Anand B.K., Brobeck J.R. Localization of a «feeding center» in the hypothalamus of the rat. Proc Soc Exp Biol Med. 1951; 77(2): 323–24. doi: 10.3181/00379727-77-18766.

  26. Ahima R.S., Bjorbaek C., Osei S., Flier J.S. Regulation of neuronal and glial proteins by leptin: Implications for brain development. Endocrinology. 1999; 140(6): 2755–62. doi: 10.1210/endo.140.6.6774.

  27. Cowley M.A., Smart J.L., Rubinstein M. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001; 411(6836): 480–84. doi: 10.1038/35078085.

  28. Wang P., Loh K.H., Wu M. et al. A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue. Nature. 2020; 583(7818): 839–44. doi: 10.1038/s41586-020-2527-y.

  29. Li C., Meng F., Lei Y. et al. Leptin regulates exon-specific transcription of the BDNF gene via epigenetic modifications mediated by an AKT/P300 HAT cascade. Mol Psychiatry. 2021; 26(8): 3701–22. doi: 10.1038/s41380-020-00922-0.

  30. Monteleone P., Maj M. Dysfunctions of leptin, ghrelin, BDNF and endocannabinoids in eating disorders: beyond the homeostatic control of food intake. Psychoneuroendocrinology. 2013; 38(3): 312–30. doi: 10.1016/j.psyneuen.2012.10.021.

  31. Никанорова А.А., Барашков Н.А., Находкин С.С. с соавт. Анализ уровня циркулирующего в крови лептина в популяции якутов. Вопросы биологической, медицинской и фармацевтической химии. 2020; 5: 10–14. [Nikanorova A.A., Barashkov N.A., Nahodkin S.S. et al. Analysis of level of leptin circulating in blood in the Yakut population. 2020; 5: 10–14 (In Russ.)]. https://dx.doi.org/10.29296/25877313-2020-05-02.

  32. Никанорова А.А., Готовцев Н.Н., Барашков Н.А. с соавт. Уровень циркулирующего в крови лептина у молодых якутов в зависимости от индекса массы тела. Якутский медицинский журнал. 2020; 4: 16–19. [Nikanorova A.A., Gotovtsev N.N., Barashkov N.A. et al. Circulating levels of leptin in blood of young Yakuts depending on body mass index. Yakutskiy meditsinskiy zhurnal = Yakutsk Medical Journal. 2020; 4: 16–19 (In Russ.)]. https://dx.doi.org/10.25789/YMJ.2020.72.04.

  33. Couillard C., Mauriege P., Prud’homme D. et al. Plasma leptin concentrations: Gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia. 1997. 40(10): 1178–84. doi: 10.1007/s001250050804.

  34. Fox C.S., Esparza J., Nicolson M. et al. Is a low leptin concentration, a low resting metabolic rate, or both the expression of the «thrifty genotype»? Results from Mexican Pima Indians. Am J Clin Nutr. 1998; 68(5): 1053–57. doi: 10.1093/ajcn/68.5.1053.

  35. Chan J.L., Heist K., DePaoli A.M. et al. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003; 111(9): 1409–21. doi: 10.1172/JCI17490.

  36. Esteghamati A., Khalilzadeh O., Ashraf H. et al. Physical activity is correlated with serum leptin independent of obesity: results of the national surveillance of risk factors of noncommunicable diseases in Iran (SuRFNCD-2007). Metabolism. 2010; 59(12): 1730–35. doi: 10.1016/j.metabol.2010.04.016.

  37. Guzman D.D., Marchau L.A.M., Reyes J.L. et al. Leptin levels and nutritional status of indigenous Tepehuan and Mestizo subjects in Durango, Mexico. Dis Markers. 2014; 2014: 974503. doi: 10.1155/2014/974503.

  38. MacIver N.J., Thomas S.M., Green C.L., Worley G. Increased leptin levels correlate with thyroid autoantibodies in nonobese males. Clin. Endocrinol (Oxf). 2016; 85(1): 116–21. doi: 10.1111/cen.12963.

  39. Koca T.T., Berk E., Seyithanoglu M. et al. Relationship of leptin, growth hormone, and insulin-like growth factor levels with body mass index and disease severity in patients with fibromyalgia syndrome. Acta Neurol Belg. 2020; 120(3): 595–99. doi: 10.1007/s13760-018-01063-6.

  40. Farr O.M., Chiang-Shan R.L., Mantzoros C.S. Central nervous system regulation of eating: Insights from human brain imaging. Metabolism. 2016; 65(5): 699–713. doi: 10.1016/j.metabol.2016.02.002.

  41. Scott M.M., Lachey J.L., Sternson S.M. et al. Leptin targets in the mouse brain. J Comp Neurol. 2009; 514(5): 518–32. doi: 10.1002/cne.22025.

  42. Zhou Y., Rui L. Leptin signaling and leptin resistance. Front Med. 2013; 7(2): 207–22. doi: 10.1007/s11684-013-0263-5.

  43. King B.M. Amygdaloid lesion-induced obesity: relation to sexual behavior, olfaction, and the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2006; 291(5): R1201–14. doi: 10.1152/ajpregu.00199.2006.

  44. Kim K.W., Sohn J.W., Kohno D. et al. SF-1 in the ventral medial hypothalamic nucleus: a key regulator of homeostasis. Mol Cell Endocrinol. 2011; 336(1–2): 219–23. doi: 10.1016/j.mce.2010.11.019.

  45. Xu B., Goulding E.H., Zang K. et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003; 6(7): 736–42. doi: 10.1038/nn1073.

  46. Halaas J., Gajiwala K., Maffei M. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995; 269(5223): 543–46. doi: 10.1126/science.7624777.

  47. Liao G.Y., An J.J., Gharami K. et al. Dendritically targeted BDNF mRNA is essential for energy balance and response to leptin. Nat Med. 2012; 18(4): 564–71. doi: 10.1038/nm.2687.


About the Autors

Alena A. Nikanorova, junior researcher of the Laboratory of molecular genetics, Yakutsk Scientific Center for Complex Medical Problems. Address: 677018, Yakutsk, 6/3 Yaroslavskogo Str. E-mail: nikanorova.alena@mail.ru. ORCID: 0000-0002-7129-6633
Nikolai A. Barashkov, PhD, head of the Laboratory of molecular genetics, Yakutsk Scientific Center for Complex Medical Problems. Address: 677018, Yakutsk, 6/3 Yaroslavskogo Str. E-mail: barashkov2004@mail.ru. ORCID: 0000-0002-6984-7934
Sergei S. Nakhodkin, researcher of the research Laboratory of molecular biology, Institute of Natural Sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: sergnahod@mail.ru. ORCID: 0000-0002-6917-5760
Vera G. Pshennikova, PhD, head of the Laboratory of population genetics, Yakutsk Scientific Center for Complex Medical Problems. Address: 677018, Yakutsk, 6/3 Yaroslavskogo Str. E-mail: pshennikovavera@mail.ru. ORCID: 0000-0001-6866-9462
Nyurgun N. Gotovtsev, researcher of the Laboratory of molecular genetics, Yakutsk Scientific Center for Complex Medical Problems. Address: 677018, Yakutsk, 6/3 Yaroslavskogo Str. E-mail: donzcrew@mail.ru. ORCID: 0000-0002-4710-1592
Aisen V. Soloviev, PhD, senior researcher of scientific-research Laboratory of molecular biology, Institute of Natural Sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: nelloann@mail.ru. ORCID: 0000-0002-0664-4224
Georgy P. Romanov, researcher of scientific-research Laboratory of molecular biology, Institute of Natural Sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: gpromanov@gmail.com. ORCID: 0000-0002-2936-5818
Sargylana S. Kuzmina, PhD, associate professor of the Institute of Natural Sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: sskuzmina@bk.ru
Nikolay N. Sazonov, MD, professor of the Institute of Natural Sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: saznikol@mail.ru
Sardana A. Fedorova, MD, head of the research Laboratory of molecular biology, Institute of natural sciences of M.K. Ammosov North-Eastern University. Address: 677010, Yakutsk, 48 Kulakovskogo Str. E-mail: sardaanafedorova@mail.ru. ORCID: 0000-0002-6952-3868


Similar Articles

Back to Content

Бионика Медиа