Brain-Derived Neurotrophic Factor in Obesity and Brain Function

Brain-Derived Neurotrophic Factor in Obesity and Neurocognitive Function

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Developmental Delay; Mental Retardation; Genetic Disorder

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 93

Contacts and Locations

Study Locations

• Canada
  • Alberta, Canada
    • University of Alberta
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Subject Inclusion Criteria:

1. For PWS subjects: We will enroll 75 subjects of all ages who have diagnosis of PWS confirmed by chromosome analysis (i.e. interstitial deletion of paternally-derived chromosome 15q, uniparental maternal disomy or other chromosome 15 abnormalities). Our goal is to have 25 infants, 25 non-obese, and 25 obese subjects in order to assess the different phases associated with PWS. Subjects receiving growth hormone therapy may enroll if the dose has been stable for the preceding 6 months.
2. For MC4R subjects: We will screen up to 200 subjects for mutations of MC4R and enroll 50 subjects of all ages who have diagnosis of homozygous or heterozygous MC4R mutation confirmed by sequencing of the MC4R gene. Both functional-altering (N=25) and non-pathologic (N=25) mutations will be included.
3. For control subjects: We will enroll 125 subjects of all ages who match with PWS or MC4R subjects by age (plus-minus 10%), sex, race, and BMI percentile (plus-minus10%).

EXCLUSION CRITERIA:

Subject Exclusion Criteria:

1. For all subjects:

   1. Pregnancy
   2. Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or other condition which, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study
   3. If age >12 months, greater than 2% body weight loss in preceding 6 months
   4. Anorexiant or weight loss medication use in preceding 6 months

2. For control subjects:

   1. Chronic medical conditions anticipated to affect results or impede study participation
   2. Medication use will be reviewed on a case-by-case basis by the Principal Investigator to determine eligibility

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Serum brain-derived neurotrophic factor concentration

Secondary Outcome Measures

Outcome Measure
Body Composition, Cognitive Function

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Han JC, Reyes-Capo DP, Liu CY, Reynolds JC, Turkbey E, Turkbey IB, Bryant J, Marshall JD, Naggert JK, Gahl WA, Yanovski JA, Gunay-Aygun M. Comprehensive Endocrine-Metabolic Evaluation of Patients With Alstrom Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2707-2719. doi: 10.1210/jc.2018-00496.
• Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S. Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol. 2010 Apr;70(5):271-88. doi: 10.1002/dneu.20774.
• Wisse BE, Schwartz MW. The skinny on neurotrophins. Nat Neurosci. 2003 Jul;6(7):655-6. doi: 10.1038/nn0703-655. No abstract available.
• Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003 Jul;6(7):736-42. doi: 10.1038/nn1073.

Study record dates

Study Major Dates

• Study Start: January 9, 2012
• Study Completion: December 12, 2014

Study Registration Dates

• First Submitted: January 24, 2012
• First Submitted That Met QC Criteria: January 24, 2012
• First Posted (Estimate): January 25, 2012

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 14, 2019
• Last Verified: December 12, 2014

More Information

Terms related to this study

• Keywords: Obesity; HV; Overweight; Healthy Volunteer; Body Composition; Prader-Willi Syndrome; Energy Homeostasis; Nociception; Genetic Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Neurodevelopmental Disorders; Obesity; Intellectual Disability; Genetic Diseases, Inborn
• Other Study ID Numbers: 120051; 12-CH-0051