Developmental, nutritional and hormonal reg. of Ghrelin

这项建议的总体目标是研究食欲的神经内分泌调节， 使用食欲紊乱和肥胖的临床模型测量体重。我和我的同事发现， 患有普拉德-威利综合征（PWS）的儿童，这是一种伴有严重肥胖的遗传性疾病， 食欲旺盛，空腹和餐后生长激素释放肽水平高， 胃相反，生长激素释放肽水平在患有“外源性”肥胖症或肥胖症的儿童和成人中受到抑制。 由瘦素或黑皮质素-4受体突变引起的肥胖症。高循环浓度的 生长激素释放肽可能是PWS体重增加的发病机制的关键，因为生长激素释放肽刺激食欲， 啮齿动物和成年人的体重增加。 我们假设：（a）空腹和餐后血浆ghrelin浓度的增加先于 或与PWS儿童出现食欲紊乱和体重增加一致;（B） PWS中血浆生长素释放肽的宏量营养素调节不同于“外源性肥胖”中的调节，以及（c）长期 抑制PWS患儿血浆ghrelin可减少食物摄入、体重和脂肪量。 为了验证这些假设，我们将比较空腹胃饥饿素浓度的变化模式， 在整个婴儿期和幼儿期患有PWS的儿童在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， 碳水化合物和脂肪对PWS儿童ghrelin浓度的影响， BMI匹配的正常对照。最后，我们将确定奥曲肽长期抑制生长激素释放肽是否 减少PWS儿童的食物摄入量、体重和脂肪量，并增加能量消耗。 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

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.