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.

Trial registration: ClinicalTrials.gov NCT00339482.

Figure 1

Comparison of subjects in the Pima cohort by MC4R functional status. (A) BMI-Z (adjusted for age, sex, and percent Indian heritage) was similar for LOF vs. LOF-C and for GOF vs. GOF-C. The LOF and LOF-C groups had higher adjusted BMI-Z than the GOF and GOF-C groups. Adjusted means ± SEMs and P values from post-hoc least significant difference (LSD) pairwise comparisons are shown. (B) Serum leptin concentration (adjusted for age, sex, BMI-Z, percent Indian heritage, and sample storage time) was not significantly different between groups. (C) Serum BDNF concentration (adjusted for age, sex, BMI-Z, percent Indian heritage, and sample storage time) was not significantly different between groups. (D) Serum BDNF and leptin concentrations were positively correlated, but there was no significant difference in this relationship by MC4R functional status (P = 0.08). For (B)–(D), log values were used for calculations. For (B)–(C), back-transformed adjusted means ± 95% CIs and overall P value from ANCOVAs are shown.

Figure 2

Comparison of subjects in the Hispanic cohort by MC4R functional status. (A) BMI-Z (adjusted for age and sex) was not significantly different between LOF, controls, and GOF groups. (B) Serum leptin concentration (adjusted for age, sex, and BMI-Z) was not significantly different between groups. (C) Plasma BDNF concentration (adjusted for age, sex, and BMI-Z) was not significantly different between groups. (D) Plasma BDNF and serum leptin concentrations were not correlated within the Hispanic cohort, and there was no significant difference in this relationship by MC4R functional status (P = 0.65). For (B)–(D), log values were used for calculations. For (B)–(C), back-transformed adjusted means ± 95% CIs and overall P value from ANCOVAs are shown.