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  • Original Article
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Genetics and Epigenetics

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

International Journal of Obesity volume 38, pages 1068–1074 (2014)Cite this article

Subjects

Abstract

Background:

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown.

Objective:

The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R.

Methods:

Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped.

Results:

In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction.

Conclusions:

Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

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References

  1. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 2003; 6: 736–742.

    Article  CAS  Google Scholar 

  2. Nicholson JR, Peter JC, Lecourt AC, Barde YA, Hofbauer KG . Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function. J Neuroendocrinol 2007; 19: 974–982.

    Article  CAS  Google Scholar 

  3. Bariohay B, Roux J, Tardivel C, Trouslard J, Jean A, Lebrun B . Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control. Endocrinology 2009; 150: 2646–2653.

    Article  CAS  Google Scholar 

  4. Caruso C, Carniglia L, Durand D, Gonzalez PV, Scimonelli TN, Lasaga M . Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase A pathway. Mol Cell Endocrinol 2013; 348: 47–54.

    Article  Google Scholar 

  5. Kernie SG, Liebl DJ, Parada LF . BDNF regulates eating behavior and locomotor activity in mice. EMBO J 2000; 19: 1290–1300.

    Article  CAS  Google Scholar 

  6. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 1999; 96: 15239–15244.

    Article  CAS  Google Scholar 

  7. Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M . Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 2007; 27: 14265–14274.

    Article  CAS  Google Scholar 

  8. Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359: 918–927.

    Article  CAS  Google Scholar 

  9. Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 2006; 55: 3366–3371.

    Article  CAS  Google Scholar 

  10. Han JC, Muehlbauer MJ, Cui HN, Newgard CB, Haqq AM . Lower brain-derived neurotrophic factor in patients with prader-willi syndrome compared to obese and lean control subjects. J Clin Endocrinol Metab 2010; 95: 3532–3536.

    Article  CAS  Google Scholar 

  11. Liu H, Kishi T, Roseberry AG, Cai X, Lee CE, Montez JM et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 2003; 23: 7143–7154.

    Article  CAS  Google Scholar 

  12. Stranahan AM, Arumugam TV, Mattson MP . Lowering corticosterone levels reinstates hippocampal brain-derived neurotropic factor and Trkb expression without influencing deficits in hypothalamic brain-derived neurotropic factor expression in leptin receptor-deficient mice. Neuroendocrinology 2011; 93: 58–64.

    Article  CAS  Google Scholar 

  13. Nakagawa T, Ono-Kishino M, Sugaru E, Yamanaka M, Taiji M, Noguchi H . Brain-derived neurotrophic factor (BDNF) regulates glucose and energy metabolism in diabetic mice. Diabetes Metab Res Rev 2002; 18: 185–191.

    Article  CAS  Google Scholar 

  14. Bagnol D, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I et al. Anatomy of qan endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci 1999; 19: RC26.

    Article  CAS  Google Scholar 

  15. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 2000; 106: 271–279.

    Article  CAS  Google Scholar 

  16. Thearle MS, Muller YL, Hanson RL, Mullins M, Abdussamad M, Tran J et al. Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians. Diabetes 2012; 61: 250–257.

    Article  CAS  Google Scholar 

  17. Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, Shaw AM et al. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry 2006; 45: 7277–7288.

    Article  CAS  Google Scholar 

  18. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 2007; 16: 1837–1844.

    Article  CAS  Google Scholar 

  19. Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007; 50: 431–438.

    Article  CAS  Google Scholar 

  20. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18–24.

    Article  CAS  Google Scholar 

  21. Knowler WC, Pettitt DJ, Saad MF, Charles MA, Nelson RG, Howard BV et al. Obesity in the Pima Indians: its magnitude and relationship with diabetes. Am J Clin Nutr 1991; 53 (6 Suppl): 1543S–1551S.

    Article  CAS  Google Scholar 

  22. Butte NF, Cai G, Cole SA, Comuzzie AG . Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in the Hispanic population. Am J Clin Nutr 2006; 84: 646–654.

    Article  CAS  Google Scholar 

  23. Cole SA, Butte NF, Voruganti VS, Cai G, Haack K, Kent JW Jr et al. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. Am J Clin Nutr 2010; 91: 191–199.

    Article  CAS  Google Scholar 

  24. Tao YX . The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010; 31: 506–543.

    Article  CAS  Google Scholar 

  25. Cai G, Cole SA, Butte N, Bacino C, Diego V, Tan K et al. A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children. Obesity (Silver Spring) 2006; 14: 1596–1604.

    Article  CAS  Google Scholar 

  26. Tan K, Pogozheva ID, Yeo GS, Hadaschik D, Keogh JM, Haskell-Leuvano C et al. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology 2009; 150: 114–125.

    Article  CAS  Google Scholar 

  27. Tao YX, Segaloff DL . Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. J Clin Endocrinol Metab 2005; 90: 5632–5638.

    Article  CAS  Google Scholar 

  28. Xiang Z, Proneth B, Dirain ML, Litherland SA, Haskell-Luevano C . Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry 2010; 49: 4583–4600.

    Article  CAS  Google Scholar 

  29. Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB et al. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci USA 1980; 77: 5754–5758.

    Article  CAS  Google Scholar 

  30. Tao YX, Segaloff DL . Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 2003; 144: 4544–4551.

    Article  CAS  Google Scholar 

  31. Comuzzie AG, Cole SA, Laston SL, Voruganti VS, Haack K, Gibbs RA et al. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One 2012; 7: e51954.

    Article  CAS  Google Scholar 

  32. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 2002; 11: 1–190.

    Google Scholar 

  33. Cole TJ . The LMS method for constructing normalized growth standards. Eur J Clin Nutr 1990; 44: 45–60.

    CAS  Google Scholar 

  34. Gaunt TR, Rodriguez S, Day IN . Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'. BMC Bioinformatics 2007; 8: 428.

    Article  Google Scholar 

  35. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H et al. Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007; 25: 367–372.

    Article  CAS  Google Scholar 

  36. Webster MJ, Herman MM, Kleinman JE, Shannon Weickert C . BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan. Gene Expr Patterns 2006; 6: 941–951.

    Article  CAS  Google Scholar 

  37. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  Google Scholar 

  38. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 2002; 87: 728–734.

    Article  CAS  Google Scholar 

  39. El-Gharbawy AH, Adler-Wailes DC, Mirch MC, Theim KR, Ranzenhofer L, Tanofsky-Kraff M et al. Serum brain-derived neurotrophic factor concentrations in lean and overweight children and adolescents. J Clin Endocrinol Metab 2006; 91: 3548–3552.

    Article  CAS  Google Scholar 

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Acknowledgements

Funding for this study was provided by the International Hyperphagia Conference Best Idea Grant from the Prader–Willi Syndrome Association (USA) (JCH and JAY), by the NIH Intramural Research Programs of NICHD and NIDDK, American Diabetes Association grant 1–12-BS212 (Y-XT), NIH (R01 DK59264 and R01 DK080457 (NFB), and C06 RR013556 and C06 RR017515) and USDA/ARS under Cooperative Agreement 58–6250–51000–037. JK and JAY are Commissioned Officers of the United States Public Health Service. Clinical Trials Registry: Subjects in the Pima cohort were enrolled in observational, non-interventional studies, registered as NCT00339482. Subjects in the Hispanic cohort were enrolled in observational, non-interventional studies.

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Authors and Affiliations

  1. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA

    M G Hohenadel, M S Thearle, B A Grice, Y L Muller, L J Baier, J Krakoff & W C Knowler

  2. Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    H Huang, M-H Dai & Y-X Tao

  3. Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    L A Hunter, G I Palaguachi, Z Mou, R C Kim, M M Tsang & J C Han

  4. Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    L A Hunter, G I Palaguachi, Z Mou, R C Kim, M M Tsang, J A Yanovski & J C Han

  5. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    K Haack, V S Voruganti, S A Cole & A G Comuzzie

  6. USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA

    N F Butte

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Correspondence to J C Han.

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Hohenadel, M., Thearle, M., Grice, B. et al. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. Int J Obes 38, 1068–1074 (2014). https://doi.org/10.1038/ijo.2013.221

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