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.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hohenadel
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Thearle
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Grice
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: M-H
authors.initials: MH
authors.lastname: Dai
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: L A
authors.initials: LA
authors.lastname: Hunter
authors.affiliation: 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.
authors.forename: G I
authors.initials: GI
authors.lastname: Palaguachi
authors.affiliation: 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Mou
authors.affiliation: 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.
authors.forename: R C
authors.initials: RC
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: M M
authors.initials: MM
authors.lastname: Tsang
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Haack
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Voruganti
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Cole
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Butte
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Muller
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Baier
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Krakoff
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Phoenix, AZ, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Yanovski
authors.affiliation: 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.
authors.forename: J C
authors.initials: JC
authors.lastname: Han
mesh_terms: D000293:Adolescent; D000328:Adult; D001130:Arizona; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics / Q000706:statistics & numerical data; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D007198:Indians, North American / Q000235:genetics / Q000706:statistics & numerical data; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D009765:Obesity / Q000208:ethnology / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044105:Receptor, Melanocortin, Type 4 / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; C579455:BDNF protein, human