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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #307552

Research Project: DEVELOPMENT AND PREVENTION OF CHILDHOOD OBESITY

Location: Children's Nutrition Research Center

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

Author
item Hohenadel, M - National Institutes Of Health (NIH)
item Thearle, M - National Institutes Of Health (NIH)
item Grice, B - National Institutes Of Health (NIH)
item Huang, H - Auburn University
item Dai, M-h - Auburn University
item Tao, Y-x - Auburn University
item Hunter, L - National Institutes Of Health (NIH)
item Palaguachi, G - National Institutes Of Health (NIH)
item Mou, Z - National Institutes Of Health (NIH)
item Kim, R - National Institutes Of Health (NIH)
item Tsang, M - National Institutes Of Health (NIH)
item Haack, K - Texas Biomedical Institute
item Voruganti, V - Texas Biomedical Institute
item Cole, S - Texas Biomedical Institute
item Butte, N - Children'S Nutrition Research Center (CNRC)
item Comuzzie, A - Texas Biomedical Institute
item Muller, Y - National Institutes Of Health (NIH)
item Baier, L - National Institutes Of Health (NIH)
item Krakoff, J - National Institutes Of Health (NIH)
item Knowler, W - National Institutes Of Health (NIH)
item Yanovski, J - National Institutes Of Health (NIH)
item Han, J - National Institutes Of Health (NIH)

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/4/2013
Publication Date: 12/17/2013
Citation: Hohenadel, M.G., Thearle, M.S., Grice, B.A., Huang, H., Dai, M., Tao, Y., Hunter, L.A., Palaguachi, G.I., Mou, Z., Kim, R.C., Tsang, M.M., Haack, K., Voruganti, V.S., Cole, S.A., Butte, N.F., Comuzzie, A.G., Muller, Y.L., Baier, L.J., Krakoff, J., Knowler, W.C., Yanovski, J.A., Han, J.C. 2013. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. International Journal of Obesity. 221:1-7.

Interpretive Summary: A protein that comes from the hypothalamus called brain-derived neurotrophic factor (BDNF)is associated with obesity and appears to be controlled by actions of the specific gene - melanocortin-4 receptor (MC4R) we wanted to understand how changes in the gene (MC4R) affect the blood levels of BDNF in humans. Our goal was to compare the brain levels of BDNF in people with variations in the gene (MC4R) that cause gain in function or loss of function. We enrolled Pima Indians and Hispanic children and sequenced their DNA for variants in (MC4R). We found that the amounts of BDNF in the blood were not affected by variation in MC4R, and this tells us that blood BDNF does not directly reflect brain BDNF secretion and/or that the gene (MC4R) is not an important regulator of the BDNF levels in humans. Understanding the factors underlying appetite regulation is important for the prevention and treatment of obesity.

Technical Abstract: 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. 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. 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. 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. 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.