Macronutrient Regulation of Ghrelin and Peptide YY

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.

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.