Brain-Derived Neurotrophic Factor in Obesity and Brain Function

Developmental Delay, Genetic Disorder, Mental Retardation, Obesity

Body Composition, Obesity, Overweight, Energy Homeostasis, Nociception, Prader-Willi Syndrome, Genetic Disorder, Healthy Volunteer, HV

Background: \- Prader-Willi syndrome (PWS) and MC4R genetic mutations are two conditions that can cause problems with appetite regulation. People with PWS often have behavior and thinking problems. People with MC4R mutations may have problems with attention. These problems may be related to Brain-Derived Neurotrophic Factor (BDNF), a protein that is important for brain development. Researchers want to study people with PWS and MC4R mutations to see how BDNF is involved in these conditions. Specifically, body weight and brain function will be studied, and compared with healthy volunteers. Objectives: \- To study how BDNF affects body weight and brain function in people with PWS and MC4R mutations. Eligibility: * Individuals of any age who have Prader-Willi syndrome or MC4R genetic mutations. * Healthy volunteers of any age to act as control participants. Design: * Participants will be screened with a medical history and physical exam. Height, weight, and waist/hip circumferences will be measured. Blood samples will be taken for genetic and other tests. * Participants will fill out questionnaires about eating habits, pain perception, and sleep behavior. * Participants will keep a 3-day food diary to record all food and drinks eaten. * Tests and questionnaires will be given to study thinking, speech, movement, behavior, and mood. Some tests will be done on a computer; other tests will be on paper. Tests may also involve performing tasks with blocks and other objects. * Participants may have other tests as directed. These will include hot and cold sensitivity tests, imaging studies like x-rays, and measurements of body fat and water content. * Treatment will not be provided as part of this study.

Brain-derived neurotrophic factor (BDNF) is a protein that is important in nervous system development and function. BDNF also 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, obesity, and neurocognitive deficits. We propose to study BDNF in two hyperphagic disorders: Prader-Willi syndrome and MC4R function-altering mutations. We 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. We 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, we wish to conduct cross-sectional studies to evaluate serum BDNF concentrations, metabolism, body composition, and neurocognition in: subjects with PWS, subjects with MC4R mutations and 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.

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