Developmental, nutritional and hormonal reg. of Ghrelin

描述(由申请人提供)： 这项建议的总体目标是使用食欲紊乱和肥胖的临床模型来研究神经内分泌对食欲和体重的调节。我和我的同事们发现，患有普拉德-威利综合征(PWS)的儿童空腹和餐后Ghrelin水平都很高，这是一种在胃中产生的促食欲素。PWS是一种遗传性疾病，伴随着严重的肥胖和贪婪的食欲。相反，在患有“外源性”肥胖症或由瘦素或黑素皮质素-4受体突变引起的肥胖症的儿童和成人中，生长激素水平受到抑制。Ghrelin的高循环浓度可能在PWS体重增加的发病机制中起关键作用，因为Ghrelin刺激啮齿动物和成人的食欲和体重增加。 我们假设：(A)在PWS儿童出现食欲紊乱和体重增加之前或同时，空腹和餐后血浆Ghrelin浓度升高；(B)PWS儿童血浆Ghrelin的宏观营养素调节不同于“外源性肥胖”；以及(C)PWS儿童长期抑制血浆Ghrelin将减少食物摄入量、体重和脂肪质量。 为了验证这些假设，我们将比较患有PWS的儿童在整个婴儿期和早期阶段空腹Ghrelin浓度的变化模式，以及其他正常(非肥胖和肥胖)婴儿和儿童的变化模式。然后，我们将比较饮食碳水化合物和脂肪对PWS儿童Ghrelin浓度的抑制作用，并与年龄、性别和BMI匹配的正常对照组进行比较。最后，我们将确定奥曲肽长期抑制Ghrelin是否会减少PWS儿童的食物摄入量、体重和脂肪质量，并增加能量消耗。 我们的研究应该为生长激素和其他激素和脂肪细胞因子在调节Prader-Willi综合征儿童和正常儿童体重中的作用提供新的见解。

DESCRIPTION (provided by applicant): 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.