The overall objective of this proposal is to examine the neuroendocrine regulation of appetite and body weight using a clinical model of disordered appetite and obesity. My colleagues and I discovered that children with Prader-Willi Syndrome (PWS), a genetic disorder accompanied by severe obesity and voracious appetite, have high fasting and post-prandial levels of ghrelin, an orexigenic peptide produced in the stomach. In contrast, ghrelin levels are suppressed in children and adults with """"""""exogenous"""""""" obesity or with obesity caused by mutations in leptin or the melanocortin-4 receptor. The high circulating concentrations of ghrelin may be critical for the pathogenesis of weight gain in PWS because ghrelin stimulates appetite and weight gain in rodents and human adults. We hypothesize that: (a) increases in fasting and post-prandial plasma ghrelin concentrations precede or coincide with the emergence of disordered appetite and weight gain in children with PWS; (b) the macronutrient regulation of plasma ghrelin in PWS differs from that in """"""""exogenous obesity"""""""" and (c) long-term suppression of plasma ghrelin in children with PWS will reduce food intake, body weight and fat mass. To test these hypotheses, we will compare the pattern of change in fasting ghrelin concentrations in children with PWS throughout infancy and early childhood with the pattern of change in otherwise normal (nonobese and obese) infants and children. We will then compare the suppressive effects of dietary carbohydrate and fat on ghrelin concentrations in children with PWS with those in age-, gender- and BMI-matched normal controls. Finally, we will determine if long-term suppression of ghrelin by octreotide reduces food intake, body weight and fat mass and increases energy expenditure in children with PWS. Our studies should provide novel insights into the role of ghrelin and other hormones and adipocytokines in the regulation of body weight in both children with Prader-willi syndrome and normal children.
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