METABOLIC ADAPTATIONS OF OBESITY WITH GH ADMINISTRATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在美国，肥胖的流行已经达到了令人担忧的程度，甚至是流行病的程度。尽管每年在减肥相关产品上花费数十亿美元，但仍有超过5000万美国人超重或肥胖。生长激素（GH）和胰岛素是蛋白质合成以及脂质和葡萄糖代谢的主要调节因子。肥胖受试者血清生长激素降低主要是由于生长激素脉冲幅度降低。因此，肥胖个体的生长激素分泌不仅在绝对意义上减少，而且生长激素向外周组织的呈现模式也从高搏动型变为无搏动型生长激素分泌，即类似于低速率恒定输注。生长激素的分泌模式已被证明是调节肝脏和骨骼代谢的一个独立因素。因此，生长激素搏动的类似作用也可能是调节能量分布的重要性，因此，不同模式的生长激素向外周组织呈现，在脂肪和蛋白质的选择性代谢活动中发挥不同的作用。生长激素分泌的损害是由于内脏脂肪过多。目前尚不清楚生长激素的使用是否会增加脂肪分解率，或者生长激素的使用方式是否会改变脂肪分解。单次输注生长激素可刺激肌肉蛋白质合成，而长期输注则可减少尿尿素排泄并增加全身蛋白质合成。生长激素的管理减少蛋白质分解和促进瘦体重随着时间的推移。我们建议研究连续输注生长激素和脉冲输注生长激素是否会对调节肌肉燃料代谢的蛋白质合成、脂肪分解、葡萄糖摄取和胰岛素敏感性产生不同的影响。我们将研究24名肥胖受试者。他们将被允许在GCRC进行为期9天的两次访问。在持续或搏动GH输注过程中，他们将通过特殊的代谢试验进行研究。对代谢的影响将通过输注脂肪、葡萄糖和蛋白质后的血液检查来评估，肌肉的反应将通过肌肉活检来评估。本研究结果将为更好地理解生长激素在肥胖受试者代谢适应中的作用铺平道路

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the United States, the prevalence of obesity has reached alarming and even epidemic proportions. Despite the billions of dollars spent annually on weight-loss related products more than 50 million Americans are either overweight or obese. Growth hormone (GH) and insulin are primary regulators of protein synthesis, as well as lipid and glucose metabolism. Serum GH is reduced in obese subjects primarily as a result of reduced GH pulse amplitude. Thus, GH secretion in obese individuals is not only decreased in absolute terms but the pattern of GH presentation to the peripheral tissues is changed from a highly pulsatile one to absence of pulsatile GH secretion, i.e resembling a low rate constant infusion. The pattern of GH secretion has been shown to be an independent factor in the regulation of liver and bone metabolism. Thus a similar role of GH pulsatility may also be of importance of regulating energy distribution whereby different patterns of GH presentation to the peripheral tissues playing divergent roles in selective metabolic activities of fat and protein. The impairment in GH secretion is due to the excess of visceral fat. It is not clear whether administration of GH will increase lipolytic(breakdown of fat) rate or whether mode of administration of GH alters lipolysis. A single infusion of GH stimulates muscle protein synthesis, whereas more prolonged administration reduces urinary urea excretion and increases whole body protein synthesis. Administration of GH diminishes protein breakdown and promotes lean body mass with time. We propose to study whether giving Growth hormone as continuous vs. pulsatile infusion will have differential effects on protein synthesis, lipolysis, glucose uptake and insulin sensitivity involved in regulating fuel metabolism in muscle. We will study 24 obese subjects. They will be admitted to GCRC for 9 days in total over 2 visits. They will be studied with special metabolic tests during continuous or pulsatile GH infusion administration . The effects on metabolism will be evaluated by blood tests following infusions of fat, glucose and protein and response of muscles will be evaluated with muscle biopsy. The results of this study will pave the way for better understanding of the role of GH in metabolic adaptation in obese subje