Brain-Derived Neurotrophic Factor in Human Subjects with Function-Altering Melanocortin-4 Receptor Variants

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: To compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants to 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±SD]: age 15.7±6.5y, BMI-Z 1.63±1.03), and 69 subjects of Hispanic heritage (10.8±3.6y, BMI-Z 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding, and cAMP 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.