Central Mediation of Growth Hormone Effects in Humans

人类生长激素效应的中枢调节

• 批准号: 10659801
• 负责人: PAMELA U FREDA
• 金额: $ 60.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-25 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659801
• 关键词: ART protein; Acromegaly; Affect; Agonist; Appetite Stimulants; Attenuated; Body Composition; Body Weight; Brain; Clinical; Clinical Treatment; Data; Development; Disease; Energy Metabolism; GLP-I receptor; Growth; Homeostasis; Hormones; Human; Hypothalamic structure; Impairment; Infusion procedures; Insulin Resistance; Insulin-Like Growth Factor I; Investigation; Leptin; Level of Evidence; Link; Longevity; Mediation; Mediator; Metabolic; Metabolism; Mus; Neurons; Neuropeptides; Nutrient; Nutritional; Obesity; Operative Surgical Procedures; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Placebos; Plasma; Process; Protein Overexpression; Rest; Role; Signal Transduction; Somatotropin; Testing; Time; Tissues; Weight; Work; antagonist; falls; glucose metabolism; human model; innovation; insight; leptin receptor; liraglutide; mortality; novel; nutrient deprivation; nutrition; pegvisomant; randomized placebo controlled study; receptor; response; stem

PROJECT SUMMARY GH and IGF-1 are well known to act on peripheral tissues to importantly influence growth, metabolism and body composition. Recently, however, our preliminary work and other data in mice have suggested that central effects of GH on the orexigenic hypothalamic neuropeptide AgRP (agouti-related protein) may be another important mechanism by which GH exerts its nutritional and metabolic effects. AgRP neurons express GH receptors and in mice, GH was shown to activate AgRP neurons to produce orexigenic responses. The current project stems from our studies in acromegaly, a human model that provides unique insights into the mechanisms of GH/IGF-1 effects. We found novel evidence that plasma levels of AgRP, a marker of hypothalamic AgRP, are higher in active acromegaly than in matched healthy subjects and are lower after surgery that reduced GH/IGF-1 or the GH receptor antagonist pegvisomant that lowered IGF-1 levels. These data suggest that GH excess increases AgRP in humans, but whether GH stimulates AgRP is unknown. Therefore, our 1st objective is to directly test the hypothesis that GH stimulates AgRP in humans. To further investigate the AgRP-GH axis, the effect of the GLP- 1R agonist liraglutide on plasma AgRP levels will also be tested in this project. Peripherally administered liraglutide targets hypothalamic GLP-1Rs and inhibits AgRP neurons in mice. Our 2nd Aim is to show that liraglutide lowers plasma AgRP levels in humans. This effect of liraglutide has not been studied in humans; thus, this study could uncover a key mechanism by which liraglutide affects body weight and metabolism. This project also explores the potential link of GH-stimulated changes in AgRP to GH-induced insulin resistance. AgRP impacts glucose metabolism in mice and plasma AgRP levels in healthy humans reflect differences in insulin resistance. In mice, in the fed state, AgRP overexpression or its’ central infusion impair glucose metabolism. Insulin resistance is a prominent feature of GH excess and GH administration is well known to induce insulin resistance early after its initiation: AgRP rise may contribute to this. By a distinct mechanism of its action, liraglutide, given along with GH, may lower AgRP and thus attenuate the insulin resistance that occurs with GH alone. Liraglutide has not been tested for treatment of the clinically important problem of GH-induced insulin resistance and thus novel, important data in this regard will be generated. We will test these hypotheses in a randomized, placebo-controlled study in which we will administer supraphysiologic and replacement GH to healthy and GH deficient humans, respectively, with and without co-administration of liraglutide. This project utilizes human models to investigate the GH-AgRP axis, potentially a key mechanism of GH action and mediator of GH-induced insulin resistance, and will provide valuable insights into the roles of AgRP and the GH-AgRP axis in human disorders of GH, nutrition and growth.

项目总结 众所周知，GH和IGF-1作用于外周组织，对生长、代谢和身体产生重要影响 组成。然而，最近，我们在小鼠身上的初步工作和其他数据表明，中枢作用 生长激素对食欲性下丘脑神经肽AgRP(刺鼠相关蛋白)的影响可能是另一个重要的因素 生长激素发挥营养和代谢作用的机制。AgRP神经元表达GH受体和 在小鼠中，GH被证明能激活AgRP神经元以产生食欲反应。当前项目源于 从我们对肢端肥大症的研究中，一个提供了对GH/IGF-1机制的独特见解的人类模型 效果。我们发现了新的证据表明，下丘脑AgRP的标记物--血浆AgRP水平在 活动期肢端肥大症患者比匹配的健康受试者更低，术后GH/IGF-1或 GH受体拮抗剂聚乙二醇胺，可降低IGF-1水平。这些数据表明，生长激素过剩增加 AgRP在人类中存在，但GH是否刺激AgRP尚不清楚。因此，我们的第一个目标是直接测试 生长激素刺激人体内AgRP的假说。为了进一步研究AgRP-GH轴，GLP- 1R激动剂利拉鲁肽对血浆AgRP水平的影响也将在本项目中进行测试。外周给药 利拉鲁肽靶向下丘脑GLP-1RS并抑制小鼠的AgRP神经元。我们的第二个目标是证明 利拉鲁肽可降低人体血浆AgRP水平。利拉鲁肽的这种作用还没有在人体上研究过；因此， 这项研究可能揭示利拉鲁肽影响体重和新陈代谢的一个关键机制。这个项目 还探讨了生长激素刺激的AgRP变化与生长激素诱导的胰岛素抵抗之间的潜在联系。AgRP 对小鼠葡萄糖代谢和健康人血浆AgRP水平的影响反映了胰岛素的差异 抵抗。在小鼠中，在喂养状态下，AgRP过表达或其中央输注会损害葡萄糖代谢。 胰岛素抵抗是生长激素过多的一个显著特征，众所周知，服用生长激素会导致胰岛素 启动后早期的耐药性：AgRP的上升可能是导致这种情况的原因之一。通过其独特的作用机制， 利拉鲁肽与生长激素一起服用可能会降低AgRP，从而减轻生长激素引起的胰岛素抵抗。 独自一人。利拉鲁肽尚未被用于治疗生长激素诱导的胰岛素这一临床重要问题 将产生抗药性，从而产生这方面的新的、重要的数据。我们将在一个 随机、安慰剂对照研究，在该研究中，我们将给予超生理和替代生长激素 健康人和生长激素缺乏者，分别在联合服用和不联合服用利拉鲁肽的情况下。这个项目 利用人体模型研究GH-AgRP轴，这可能是GH作用和中介的关键机制 对生长激素诱导的胰岛素抵抗的影响，并将为深入了解AgRP和GH-AgRP的作用提供有价值的见解 轴在人类生长激素、营养和生长方面的紊乱。