Obesity, Prader Willi Syndrome
Conditions
Keywords
Obesity, Orexigen, Insulin, Leptin, Adiponectin, Growth hormone replacement
Brief summary
The hyperghrelinemia of children with PWS provides a unique model by which to explore the hormonal and metabolic effects of orexigenic hormones in normal and pathologic conditions. An important question to be addressed by this proposed research includes the macro-nutrient regulation of ghrelin and PYY in obese children and children with PWS. As ghrelin antagonists are considered potential future anti-obesity agents, it is essential to gain understanding of the developmental, nutritional and hormonal regulation of this important orexigenic hormone in children.
Detailed description
Obesity continues to be a prevalent health concern affecting every race of the American population. Studies show that obese children are likely to become obese adults. Also, recent studies report significant years of life lost due to the impact of being an obese adult . Thus, insights into the pathogenesis of childhood obesity and preventative measures are needed to combat the inevitable increase in worldwide incidence of obesity and its associated co-morbidities. Ghrelin is a 28 amino acid acylated peptide which is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), a hypothalamic G-protein-coupled receptor. Enteroendocrine cells (X/A-like cells) of the stomach are the major site of ghrelin synthesis, although a minor proportion of ghrelin synthesis occurs in other sites such as the hypothalamus, pituitary, duodenum, jejunum and lung. Secreted in response to meals, ghrelin stimulates feeding through activation of anabolic neurons in the hypothalamic arcuate nucleus that co-express neuropeptide Y (NPY) and agouti-related protein (Agrp). Ghrelin relays its information from the GI tract to specific nuclei in the hypothalamus via the gastric afferent vagal nerve. Studies in rodents support the premise that ghrelin is involved in energy balance. In humans, physiological levels of ghrelin influence energy homeostasis in humans.The rise in plasma ghrelin concentrations during fasting may play a role in meal initiation and body weight regulation. Nearly all other forms of obesity are associated with low ghrelin levels. Paradoxically, researchers discovered that ghrelin levels in adults and children with PWS are 3-5 times higher than those in age- and BMI-matched controls. Hyperghrelinemia may thus play a causal role in the hyperphagia and obesity of PWS. The hyperghrelinemia of children with PWS provides a unique model by which to explore the hormonal and metabolic effects of orexigenic hormones in normal and pathologic condtions. An important question to be addressed by this proposed research includes the macro-nutrient regulation of ghrelin in normal children and children with PWS. As ghrelin antagonists are considered potential future anti-obesity agents, it is essential to gain understanding of the developmental, nutritional and hormonal regulation of this important orexigenic hormone in children.
Interventions
65% carbohydrate, 17% protein, and 18% fat
OTHERHigh fat meal
58% fat, 17% protein, and 25% carbohydrate
Sponsors
National Institutes of Health (NIH)
Canadian Institutes of Health Research (CIHR)
Foundation for Prader-Willi Research
Stollery Children's Hospital Foundation
Alberta Diabetes Institute
Sarah W. Stedman Nutrition and Metabolism Center
American Diabetes Association
Duke Children's Miracle Network
National Center for Research Resources (NCRR)
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of PWS confirmed by chromosome analysis (i.e. interstitial deletion of paternally-derived chromosome 15Q, uniparental maternal disomy or other chromosome 15 abnormalities) or normal control 2. Subjects with simple obesity 3. Ages 5 years to 17 years 4. Written informed consent and assent obtained and willingness to comply with the study schedule and procedures. 5. Free T4, TSH values in the normal range (either endogenous or with thyroxine replacement)
Exclusion criteria
1. Patients with any other clinically significant disease that would have an impact on body composition including diabetes mellitus, chronic inflammatory bowel disease, chronic severe liver or kidney disease or neurologic disorders 2. Concomitant use of an investigational drug in the past year 3. Patients with an active malignancy 4. Parent or legal guardian unable to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in ghrelin levels | 4 hours | The change in ghrelin levels will be measured before and after meal consumption in children with PWS, and healthy obese controls. Following an overnight 8 hour fast, subjects will be given either a high carbohydrate or high fat meal. Subjects will be allowed 25 minutes to consume everything on their food tray. Blood samples will be obtained before the meal (fasting) and every 30 minutes thereafter for 4 hours. |
| Change in PYY concentrations | 4 hours | The change in PYY concentration levels will be measured before and after meal consumption in children with PWS, and healthy obese controls. Following an overnight 8 hour fast, subjects will be given either a high carbohydrate or high fat meal. Subjects will be allowed 25 minutes to consume everything on their food tray. Blood samples will be obtained before the meal (fasting) and every 30 minutes thereafter for 4 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Insulin-like growth factor 1 (IGF-1) levels | Baseline | Baseline Insulin-like growth factor 1 (IGF-1) levels will be measured fasting before the meal in children with PWS, and healthy obese controls |
| Neuropeptide Y (NPY) | Baseline | Baseline Neuropeptide Y (NPY) levels will be measured fasting before the meal in children with PWS, and healthy obese controls |
| Gastric inhibitory polypeptide (GIP) | Baseline | Baseline Gastric inhibitory polypeptide (GIP) levels will be measured fasting before the meal in children with PWS, and healthy obese controls |
| Glucagon-like peptide-1 (GLP-1) | Baseline | Baseline Glucagon-like peptide-1 (GLP-1) levels will be measured fasting before the meal in children with PWS, and healthy obese controls |
Countries
United States
Outcome results
None listed