Central Mediation of Growth Hormone Effects in Humans

项目摘要 众所周知，GH和IGF-1作用于外周组织，对生长、代谢和身体有重要影响。 混合物.然而，最近，我们的初步工作和小鼠的其他数据表明， GH对下丘脑神经肽AgRP（刺豚鼠相关蛋白）的影响可能是另一个重要的 GH发挥其营养和代谢作用的机制。AgRP神经元表达GH受体， 在小鼠中，显示GH激活AgRP神经元以产生食欲反应。目前的项目源于 从我们对肢端肥大症的研究中，这是一种对GH/IGF-1机制提供独特见解的人类模型， 方面的影响.我们发现了新的证据，即下丘脑AgRP的标志物AgRP的血浆水平在老年人中较高， 活动性肢端肥大症的患者比匹配的健康受试者更低，并且在手术后降低GH/IGF-1或 GH受体拮抗剂pegvisomant降低IGF-1水平。这些数据表明，GH过量增加 人AgRP，但是否GH刺激AgRP是未知的。因此，我们的第一个目标是直接测试 假设GH刺激人类AgRP。为了进一步研究AgRP-GH轴，研究了GLP-1对AgRP-GH轴的影响。 本项目还将检测1R激动剂利拉鲁肽对血浆AgRP水平的影响。外周给药 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表明， 利拉鲁肽可降低人体血浆AgRP水平。尚未在人体中研究利拉鲁肽的这种作用;因此， 这项研究可能揭示利拉鲁肽影响体重和代谢的关键机制。这个项目 还探讨了GH刺激的AgRP变化与GH诱导的胰岛素抵抗的潜在联系。AgRP 影响小鼠的葡萄糖代谢，健康人的血浆AgRP水平反映了胰岛素水平的差异。 阻力在小鼠中，在进食状态下，AgRP过表达或其中枢输注损害葡萄糖代谢。 胰岛素抵抗是GH过量的一个显著特征，并且众所周知GH给药可诱导胰岛素分泌 在其开始后的早期抵抗：AgRP升高可能对此有贡献。通过其独特的作用机制， 利拉鲁肽沿着GH给药，可降低AgRP，从而减轻GH引起的胰岛素抵抗 一个人尚未对利拉鲁肽治疗GH诱导胰岛素的临床重要问题进行试验 将产生这方面的新的、重要的数据。我们将在一个 一项随机、安慰剂对照研究，我们将给予超生理和替代GH， 健康和GH缺乏的人，分别与和不与利拉鲁肽联合给药。这个项目 利用人体模型研究GH-AgRP轴，可能是GH作用和介导的关键机制 的GH诱导的胰岛素抵抗，并将提供有价值的见解AgRP和GH-AgRP的作用， 轴在人类生长激素，营养和生长障碍。

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.