Developmental, nutritional and hormonal reg. of Ghrelin

这项建议的总体目标是检查食欲和神经内分泌的调节 体重使用食欲紊乱和肥胖的临床模型。我和我的同事发现 患有普拉德-威利综合征(PWS)的儿童，这是一种遗传性疾病，伴有严重的肥胖和 食欲旺盛，有很高的空腹和餐后Ghrelin水平，这是一种在 胃。相比之下，患有“外源性”肥胖症的儿童和成人或患有 由瘦素或黑素皮质素-4受体突变引起的肥胖。较高的循环浓度 Ghrelin可能在PWS体重增加的发病机制中起关键作用，因为Ghrelin刺激食欲和 啮齿动物和成人的体重增加。 我们假设：(A)空腹和餐后血浆Ghrelin浓度升高先于 或恰逢PWS儿童出现食欲紊乱和体重增加； PWS患者血浆Ghrelin的常量营养调节不同于“外源性肥胖”和(C)长期 抑制PWS儿童的血浆Ghrelin将减少食物摄入量、体重和脂肪质量。 为了验证这些假设，我们将比较空腹Ghrelin浓度的变化模式 患有PWS的儿童在整个婴儿期和儿童早期都有其他方面正常的变化模式 (非肥胖和肥胖)婴儿和儿童。然后我们将比较饮食的抑制作用 不同年龄、性别和性别的PWS儿童糖和脂肪对Ghrelin浓度的影响 体重指数匹配的正常对照组。最后，我们将确定奥曲肽对ghrelin的长期抑制作用 减少PWS儿童的食物摄入量、体重和脂肪质量，增加能量消耗。 我们的研究应该为Ghrelin和其他激素的作用提供新的见解 脂肪细胞因子在Prader-Willi综合征和正常儿童体重调节中的作用 孩子们。

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.