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.

项目概要 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 然而，最近我们的初步工作和小鼠的其他数据表明，中枢效应。 GH 对促进食欲的下丘脑神经肽 AgRP（agouti 相关蛋白）的影响可能是另一个重要因素 GH 发挥其营养和代谢作用的机制。 在小鼠中，GH 被证明可以激活 AgRP 神经元以产生食欲反应。 来自我们对肢端肥大症的研究，这种人体模型为 GH/IGF-1 机制提供了独特的见解 我们发现新的证据表明，AgRP（下丘脑 AgRP 的标志物）的血浆水平在以下人群中较高。 与匹配的健康受试者相比，活动性肢端肥大症患者的活动性肢端肥大症在减少 GH/IGF-1 或 GH 受体拮抗剂培维索孟可降低 IGF-1 水平。这些数据表明 GH 过量会增加。 人类中的 AgRP，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。 GH 刺激人类 AgRP 的假设 为了进一步研究 AgRP-GH 轴、GLP- 的作用。 1R 激动剂利拉鲁肽对血浆 AgRP 水平的影响也将在该项目中进行外周给药测试。 利拉鲁肽靶向小鼠下丘脑 GLP-1R 并抑制 AgRP 神经元。我们的第二个目标是证明这一点。 利拉鲁肽可降低人体血浆 AgRP 水平，因此尚未在人体中研究过利拉鲁肽的这种作用。 这项研究可以揭示利拉鲁肽影响体重和新陈代谢的关键机制。 还探讨了 GH 刺激的 AgRP 变化与 GH 诱导的胰岛素抵抗之间的潜在联系。 影响小鼠的葡萄糖代谢，健康人的血浆 AgRP 水平反映了胰岛素的差异 在小鼠中，在进食状态下，AgRP 过度表达或其中枢输注会损害葡萄糖代谢。 胰岛素抵抗是 GH 过量的一个显着特征，众所周知 GH 给药会诱导胰岛素分泌 其启动后早期的耐药性：AgRP 的升高可能通过其独特的作用机制促成这一点。 利拉鲁肽与 GH 一起服用可能会降低 AgRP，从而减轻 GH 引起的胰岛素抵抗 尚未测试利拉鲁肽单独治疗 GH 诱导的胰岛素这一临床重要问题。 阻力，因此将产生这方面的新颖的、重要的数据，我们将在一个测试中测试这些假设。 随机、安慰剂对照研究，我们将给予超生理和替代 GH 健康人和 GH 缺乏的人，分别服用和不服用利拉鲁肽这个项目。 利用人体模型研究 GH-AgRP 轴，它可能是 GH 作用和介质的关键机制 GH 诱导的胰岛素抵抗，并将为 AgRP 和 GH-AgRP 的作用提供有价值的见解 人类 GH、营养和生长失调的轴。