Growth hormone and adult physiology

描述（由申请人提供）：生长激素（GH）由垂体前叶的生长激素产生，并释放到全身循环中，刺激多个靶组织产生胰岛素样生长因子I （IGF-I）。生长激素和igf - 1协同作用介导细胞功能的各个方面。在正常人中，出生后循环GH/ igf - 1水平稳步上升，在青春期周围达到平稳期，然后以每10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。基于人类和动物对生长激素缺乏症（GHD）代谢影响的研究，无论是否替代生长激素或igf - 1，很明显生长激素可以抑制脂肪积累并促进蛋白质积累，而igf - 1的代谢作用类似于胰岛素。据报道，生长激素和igf - 1对胰腺b细胞功能、心血管功能和骨重塑也有积极作用。GHD患者替代生长激素的代谢益处助长了正常健康成人使用和滥用生长激素以增强身体形象和运动表现，同时也为老年人和/或肥胖个体替代生长激素以帮助对抗代谢疾病提供了理论依据。尽管生长激素对成人有潜在的积极作用，但在生理水平上，生长激素是否会降低胰岛素敏感性、加剧癌症和缩短寿命，仍存在争议。内源性GH在维持成年人健康或促进疾病方面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管理；1)发育性GHD，可能无法反映性成熟后GH下降的后果；2)成人发病的GHD （AOGHD）经常伴有其他垂体缺陷。因此很难确定哪些变化是由生长激素损失引起的。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的具体影响区分开来。为了避免这些问题，更准确地定义内源性生长激素在成人（病理）生理学中的重要性，目前的建议将利用一种独特的基因工程小鼠模型来研究成人发病的孤立性GHD （AOiGHD）。初步研究表明，当给AOiGHD小鼠喂食低脂饮食时，脂肪量增加，但全身胰岛素敏感性提高。然而，饮食诱导的肥胖AOiGHD小鼠出现葡萄糖耐受不良，这与低喂养和空腹胰岛素水平有关，这表明生长激素/ igf - 1在维持b细胞功能方面也很重要。考虑到多个器官系统参与维持葡萄糖稳态，本系列研究将采用综合方法来确定：1)AOiGHD在何种水平上影响b细胞功能（胰岛素表达、增殖、新生和/或凋亡）；2)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还是由于组织特异性改变(肝脏、脂肪、3)确定AOiGHD是否会影响急性禁食/再喂养或长期饮食引起的体重减轻时的全身代谢和体重变化。从这些研究中获得的知识将提供关于生长激素替代疗法的益处或风险的重要信息。

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.