Brain-Derived Neurotrophic Factor in Prader-Willi Syndrome and MC4R Function-Altering Mutations

Joan C. Han, M.D., Senior Clinical Fellow, Unit on Growth and Obesity

Jack A. Yanovski, M.D., Ph.D., Head, Unit on Growth and Obesity

Program in Developmental Endocrinology and Genetics

Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH 

Abstract: Brain-derived neurotrophic factor (BDNF) is a protein that is important in nervous system development and function. BDNF is well-expressed in the hypothalamus, a key region in the brain for energy homeostasis, and appears to function downstream of the leptin-melanocortin signaling pathway to control appetite. In both animals and humans, diminished BDNF function is associated with hyperphagia and obesity. They propose to study BDNF in two hyperphagic disorders: Prader-Willi syndrome and MC4R function-altering mutations. They hypothesize that patients with PWS may have increased BDNF during infancy, followed by a decline in BDNF that precedes the onset of hyperphagia and persists after the onset of obesity. They also hypothesize that patients with MC4R mutations will have decreased BDNF, the severity of which will be associated with the degree of MC4R functional loss caused by the specific mutation(s) in each individual. To test these hypotheses, they will conduct 2 cross-sectional studies comparing serum BDNF concentrations in: 1) 75 subjects with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 healthy control subjects matched for age, sex, race, and BMI; 2) 50 subjects with MC4R mutations and 50 healthy control subjects matched for age, sex, race, and BMI. If alterations in BDNF are found to be associated with PWS and/or MC4R mutations, these investigations could lead to future studies of BDNF receptor agonists as mechanism-specific pharmacologic therapy for hyperphagia and obesity in PWS and MC4R mutations, or BDNF receptor antagonists for failure-to-thrive in neonatal PWS. 

Hypotheses:

1) Patients with PWS will have increased BDNF during infancy, followed by a decline in BDNF that will precede the onset of hyperphagia and persist after the onset of obesity.

2) Patients with MC4R mutations will have decreased BDNF, the severity of which will be associated with the degree of MC4R functional loss caused by the specific mutation(s) in each individual. 

Significance: These studies will further our understanding of the role of BDNF in human energy homeostasis. If alterations in BDNF are found to be associated with PWS and/or MC4R mutations, these investigations could lead to future studies of BDNF receptor agonists as mechanism-specific pharmacologic therapy for hyperphagia and obesity in PWS and MC4R mutations, or BDNF receptor antagonists for failure-to-thrive in neonatal PWS.