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

M. G. Hohenadel, M. S. Thearle, B. A. Grice, H. Huang, M. H. Dai, Y. X. Tao, L. A. Hunter, G. I. Palaguachi, Z. Mou, R. C. Kim, M. M. Tsang, K. Haack, V. S. Voruganti, S. A. Cole, N. F. Butte, A. G. Comuzzie, Y. L. Muller, L. J. Baier, J. Krakoff, W. C. Knowler & 2 others J. A. Yanovski, Joan Han

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1068-1074
Number of pages7
JournalInternational Journal of Obesity
Volume38
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Receptor, Melanocortin, Type 4
Brain-Derived Neurotrophic Factor
Potassium Iodide
human brain-derived neurotrophic factor
Genotype
Hispanic Americans
Single Nucleotide Polymorphism
Body Mass Index
Serum

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. / Hohenadel, M. G.; Thearle, M. S.; Grice, B. A.; Huang, H.; Dai, M. H.; Tao, Y. X.; 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, Joan.

In: International Journal of Obesity, Vol. 38, No. 8, 01.01.2014, p. 1068-1074.

Research output: Contribution to journalArticle

Hohenadel, MG, Thearle, MS, Grice, BA, Huang, H, Dai, MH, Tao, YX, Hunter, LA, Palaguachi, GI, Mou, Z, Kim, RC, Tsang, MM, Haack, K, Voruganti, VS, Cole, SA, Butte, NF, Comuzzie, AG, Muller, YL, Baier, LJ, Krakoff, J, Knowler, WC, Yanovski, JA & Han, J 2014, 'Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants', International Journal of Obesity, vol. 38, no. 8, pp. 1068-1074. https://doi.org/10.1038/ijo.2013.221
Hohenadel, M. G. ; Thearle, M. S. ; Grice, B. A. ; Huang, H. ; Dai, M. H. ; Tao, Y. X. ; 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, Joan. / Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. In: International Journal of Obesity. 2014 ; Vol. 38, No. 8. pp. 1068-1074.
@article{53b29f35e3924edab18749648dab398f,
title = "Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants",
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.",
author = "Hohenadel, {M. G.} and Thearle, {M. S.} and Grice, {B. A.} and H. Huang and Dai, {M. H.} and Tao, {Y. X.} and Hunter, {L. A.} and Palaguachi, {G. I.} and Z. Mou and Kim, {R. C.} and Tsang, {M. M.} and K. Haack and Voruganti, {V. S.} and Cole, {S. A.} and Butte, {N. F.} and Comuzzie, {A. G.} and Muller, {Y. L.} and Baier, {L. J.} and J. Krakoff and Knowler, {W. C.} and Yanovski, {J. A.} and Joan Han",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/ijo.2013.221",
language = "English (US)",
volume = "38",
pages = "1068--1074",
journal = "International Journal of Obesity",
issn = "0307-0565",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

AU - Hohenadel, M. G.

AU - Thearle, M. S.

AU - Grice, B. A.

AU - Huang, H.

AU - Dai, M. H.

AU - Tao, Y. X.

AU - Hunter, L. A.

AU - Palaguachi, G. I.

AU - Mou, Z.

AU - Kim, R. C.

AU - Tsang, M. M.

AU - Haack, K.

AU - Voruganti, V. S.

AU - Cole, S. A.

AU - Butte, N. F.

AU - Comuzzie, A. G.

AU - Muller, Y. L.

AU - Baier, L. J.

AU - Krakoff, J.

AU - Knowler, W. C.

AU - Yanovski, J. A.

AU - Han, Joan

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84905661985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905661985&partnerID=8YFLogxK

U2 - 10.1038/ijo.2013.221

DO - 10.1038/ijo.2013.221

M3 - Article

VL - 38

SP - 1068

EP - 1074

JO - International Journal of Obesity

JF - International Journal of Obesity

SN - 0307-0565

IS - 8

ER -