Growth hormone and adult physiology

性状（由申请人提供）：生长激素（GH）由垂体前叶的促生长素产生，并释放到全身循环中，在全身循环中刺激多个靶组织产生胰岛素样生长因子I（IGF-I）。GH和IGF-I协同工作以介导细胞功能的各个方面。在正常个体中，循环GH/IGF-I水平在出生后稳步上升，在青春期前后达到平台，然后以每十年约14%的速度下降。循环GH水平也随着体重增加而下降，与年龄无关。基于人类和动物研究检查GH缺乏症（GHD）的代谢影响，有和没有GH或IGF-I替代，很明显，GH可以抑制脂肪积累和促进蛋白质增加，而IGF-I的代谢作用类似于胰岛素。据报道，GH和IGF-I对胰腺B细胞功能、心血管性能和骨重建也有积极影响。GHD患者中GH替代的代谢获益促进了正常健康成人中GH的超说明书使用和滥用，以增强身体形象和运动表现，并为老年人和/或肥胖个体中GH替代提供了理论依据，以帮助对抗代谢疾病。尽管生长激素在成人中具有潜在的积极作用，但在生理水平上，生长激素是否会降低胰岛素敏感性，加剧癌症并缩短寿命仍存在争议。内源性GH在成人中维持健康或促进疾病的真正重要性仍有待澄清，因为我们的大部分知识是基于以下研究：1）正常受试者的急性或长期GH给药，1）发育性GHD，可能不反映性成熟后GH下降的后果，2）成人发作性GHD（AOGHD），通常伴有其他垂体缺陷，这使得难以确定哪些变化是由于GH损失引起的。此外，在人类中，很难将遗传、环境和生活方式的混杂影响与内分泌病理学的具体影响分开。为了避免这些问题，并更准确地定义内源性GH在成人（病理）生理学中的重要性，目前的建议将利用一个独特的基因工程小鼠模型的成人发病，孤立的GHD（AOiGHD）。初步研究表明，当AOiGHD小鼠喂食低脂饮食时，脂肪量增加，但全身胰岛素敏感性改善。然而，饮食诱导的肥胖AOiGHD小鼠发生葡萄糖耐受不良，这与低进食和空腹胰岛素水平相关，表明GH/IGF-I在维持b细胞功能方面也可能很重要。鉴于多个器官系统参与维持葡萄糖稳态，所提议的一系列研究将采取综合方法来确定1）AOiGHD在什么水平上影响b细胞功能（胰岛素表达、增殖、新生和/或凋亡），2）如果AOiGHD诱导的胰岛素敏感性增加是由于胰岛素作用的整体改善或由于组织特异性变化3）确定AOiGHD是否会影响响应于急性禁食/再喂养或长期饮食诱导的体重减轻的全身代谢和体重变化。从这些研究中获得的知识将提供有关GH替代疗法的获益或风险的重要信息。 公共卫生相关性：项目叙述与我们的现代社会有关的是确定是否正常下降生长激素（GH）发生体重增加和年龄，是代谢功能恶化的主要因素。该提案将利用一种新的成年发病的孤立性GH缺乏症（AOiGHD）小鼠模型，以确定在性别、饮食和营养可用性方面，受循环GH和IGF-I选择性减少影响最深的代谢稳态系统的关键组分。所获得的信息可用于未来的实验，以确定GH是否直接或间接作用于特定组织/细胞以介导这些效应。

DESCRIPTION (provided by applicant): Growth hormone (GH) is produced by somatotropes of the anterior pituitary gland and is released into the general circulation where it stimulates the production of insulin-like growth factor I (IGF-I) from multiple target tissues. GH and IGF-I work in concert to mediate various aspect of cellular function. In normal individuals, circulating GH/IGF-I levels steadily rise after to birth, plateau around the peripubertal period, then decline thereafter at a rate of ~14% for every decade of life. Circulating GH levels also decline with weight gain, independent of age. Based on human and animal studies examining the metabolic impact of GH deficiency (GHD), with and without GH or IGF-I replacement, it is clear that GH can inhibit fat accumulation and promote protein accretion, while the metabolic actions of IGF-I resemble those of insulin. GH and IGF-I are also reported to have positive effects on pancreatic b-cell function, cardiovascular performance and bone remodeling. The metabolic benefits of GH replacement in GHD patients has fueled the off-label use and abuse of GH in normal healthy adults to enhance body image and athletic performance, as well as providing a rationale for GH replacement in elderly and/or obese individuals to help combat metabolic disease. Despite the potential positive effects of GH in adults, there is also ongoing debate whether GH, at physiologic levels, can reduce insulin sensitivity, exacerbate cancer, and shorten lifespan. The true importance of endogenous GH in maintaining health OR promoting disease in adults, remains to be clarified since the bulk of our knowledge is based on studies of 1 ) acute or long-term GH administration in normal subjects, 1) developmental GHD, that might not reflect the consequences of GH decline after sexual maturation and 2) adult onset GHD (AOGHD) which is frequently accompanied by other pituitary defects, making it difficult to determine what changes are due specifically to GH loss. In addition, in humans it is difficult to separate out the confounding effects of genetics, environment and lifestyle from those due specifically to endocrine pathologies. To circumvent these problems and more accurately define the importance of endogenous GH in adult (patho)physiology the current proposal will utilize a unique genetically engineered mouse model of adult-onset, isolated GHD (AOiGHD). Preliminary studies demonstrated when AOiGHD mice were fed a low-fat diet, adipose mass increased, but whole body insulin sensitivity improved. However, diet-induced obese AOiGHD mice developed glucose intolerance which was associated with low fed and fasted insulin levels, suggesting GH/IGF-I may also be important in maintaining b-cell function. Given multiple organs systems are involved in maintaining glucose homeostasis, the proposed series of studies will take an integrative approach to determine 1) at what level AOiGHD impacts b-cell function (insulin expression, proliferation, neogenesis and/or apoptosis), 2) if the AOiGHD-induced increase in insulin sensitivity is due to global improvement in insulin actions or due to tissue-specific changes (liver, fat, skeletal muscle) 3) determine if AOiGHD will influence whole body metabolism and weight changes in response to acute fasting/refeeding or longterm diet-induced weight loss. Knowledge gained from these studies will provide important information regarding the benefits or risks of GH replacement therapy. PUBLIC HEALTH RELEVANCE: Project Narrative Relevant to our modern society is determining if the normal fall in growth hormone (GH) that occurs with weight gain and age, is a major contributor to the deterioration of metabolic function. This proposal will utilize a novel mouse model of adult-onset, isolated GH deficiency (AOiGHD) to identify the key components of the metabolic homeostatic system that are most profoundly affected by selective reduction in circulating GH and IGF-I, in the context of sex, diet and nutrient availability. Information gained can be used in future experiments to determine if GH acts directly or indirectly on specific tissues/cells to mediate these effects.