PMID- 24276017
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20211203
IS  - 1476-5497 (Electronic)
IS  - 0307-0565 (Print)
IS  - 0307-0565 (Linking)
VI  - 38
IP  - 8
DP  - 2014 Aug
TI  - Brain-derived neurotrophic factor in human subjects with function-altering 
      melanocortin-4 receptor variants.
PG  - 1068-74
LID - 10.1038/ijo.2013.221 [doi]
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.
FAU - Hohenadel, M G
AU  - Hohenadel MG
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Thearle, M S
AU  - Thearle MS
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Grice, B A
AU  - Grice BA
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Huang, H
AU  - Huang H
AD  - Department of Anatomy, Physiology and Pharmacology, College of Veterinary 
      Medicine, Auburn University, Auburn, AL, USA.
FAU - Dai, M-H
AU  - Dai MH
AD  - Department of Anatomy, Physiology and Pharmacology, College of Veterinary 
      Medicine, Auburn University, Auburn, AL, USA.
FAU - Tao, Y-X
AU  - Tao YX
AD  - Department of Anatomy, Physiology and Pharmacology, College of Veterinary 
      Medicine, Auburn University, Auburn, AL, USA.
FAU - Hunter, L A
AU  - Hunter LA
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Palaguachi, G I
AU  - Palaguachi GI
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Mou, Z
AU  - Mou Z
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Kim, R C
AU  - Kim RC
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Tsang, M M
AU  - Tsang MM
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Haack, K
AU  - Haack K
AD  - Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 
      USA.
FAU - Voruganti, V S
AU  - Voruganti VS
AD  - Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 
      USA.
FAU - Cole, S A
AU  - Cole SA
AD  - Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 
      USA.
FAU - Butte, N F
AU  - Butte NF
AD  - USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 
      Houston, TX, USA.
FAU - Comuzzie, A G
AU  - Comuzzie AG
AD  - Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 
      USA.
FAU - Muller, Y L
AU  - Muller YL
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Baier, L J
AU  - Baier LJ
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Krakoff, J
AU  - Krakoff J
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Knowler, W C
AU  - Knowler WC
AD  - National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institutes of Health (NIH), Phoenix, AZ, USA.
FAU - Yanovski, J A
AU  - Yanovski JA
AD  - Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
FAU - Han, J C
AU  - Han JC
AD  - 1] Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National 
      Institute of Child Health and Human Development, NIH, Bethesda, MD, USA [2] 
      Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, NIH, Bethesda, MD, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT00339482
GR  - R01 DK059264/DK/NIDDK NIH HHS/United States
GR  - C06 RR017515/RR/NCRR NIH HHS/United States
GR  - C06 RR013556/RR/NCRR NIH HHS/United States
GR  - ZIA HD008898-04/Intramural NIH HHS/United States
GR  - R01 DK080457/DK/NIDDK NIH HHS/United States
GR  - R01 DK59264/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20131126
PL  - England
TA  - Int J Obes (Lond)
JT  - International journal of obesity (2005)
JID - 101256108
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (MC4R protein, human)
RN  - 0 (Receptor, Melanocortin, Type 4)
RN  - 7171WSG8A2 (BDNF protein, human)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Arizona
MH  - Brain-Derived Neurotrophic Factor/blood/genetics/*metabolism
MH  - Child
MH  - Child, Preschool
MH  - Cohort Studies
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - *Hispanic or Latino/genetics/statistics & numerical data
MH  - Humans
MH  - Hypothalamus/*metabolism
MH  - *Indians, North American/genetics/statistics & numerical data
MH  - Longitudinal Studies
MH  - Male
MH  - Mutation
MH  - Obesity/ethnology/genetics/*metabolism
MH  - *Polymorphism, Single Nucleotide
MH  - Promoter Regions, Genetic
MH  - Receptor, Melanocortin, Type 4/blood/genetics/*metabolism
PMC - PMC4033711
MID - NIHMS538719
COIS- Disclosures: The authors have no conflicts of interest to disclose.
EDAT- 2013/11/28 06:00
MHDA- 2015/05/12 06:00
PMCR- 2015/02/01
CRDT- 2013/11/27 06:00
PHST- 2013/08/21 00:00 [received]
PHST- 2013/10/17 00:00 [revised]
PHST- 2013/11/04 00:00 [accepted]
PHST- 2013/11/27 06:00 [entrez]
PHST- 2013/11/28 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - ijo2013221 [pii]
AID - 10.1038/ijo.2013.221 [doi]
PST - ppublish
SO  - Int J Obes (Lond). 2014 Aug;38(8):1068-74. doi: 10.1038/ijo.2013.221. Epub 2013 
      Nov 26.