Impact of obesity on the growth hormone axis: Evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function
Impact of obesity on the growth hormone axis: Evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function
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DOI：
10.1210/en.2005-1549
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Kineman, Rhonda D.
中科院分区：
文献类型：
--
作者：
Luque, Raul M.;Kineman, Rhonda D.
肥胖与 GH 之间存在负相关关系。然而，尚不清楚与肥胖相关的代谢变化如何导致 GH 输出减少。这项研究检查了两种肥胖小鼠模型的 GH 轴，即瘦素缺乏 (ob/ob) 小鼠和饮食诱导肥胖 (DIO；高脂喂养) 小鼠。两种模型均表现出高血糖和高胰岛素血症，伴有 GH 表达减少以及对 GH 合成和释放很重要的垂体受体表达减少 [GHRH 受体（仅限 DIO）和 ghrelin 受体（ob/ob 和 DIO）]。这些垂体变化并不伴随下丘脑 GHRH 或生长抑素表达的变化；这表明垂体功能的改变可能部分是由系统信号的直接影响引起的。在检查的代谢和激素参数（胰岛素、葡萄糖、皮质酮、游离脂肪酸、生长素释放肽和 IGF-I）中，只有胰岛素/葡萄糖与垂体表达呈显着负相关。尽管存在全身性（骨骼肌和脂肪）胰岛素抵抗，但通过 Akt 磷酸化评估，DIO 小鼠的垂体仍然对胰岛素的急性体内作用有反应。此外，与媒介物处理的对照相比，用胰岛素处理瘦小鼠的原代垂体细胞培养物可降低 GH 释放以及 GH、GHRH 受体和 ghrelin 受体 mRNA 水平，其中垂体 mRNA 水平的抑制程度与在 DIO 小鼠中观察到的相似。这些结果加上垂体表达胰岛素受体的水平与传统上认为对胰岛素敏感的组织相当，表明高循环胰岛素水平可以直接有助于抑制肥胖状态下的 GH 合成和释放。
There is a negative relationship between obesity and GH. However, it is not known how metabolic changes, associated with obesity, lead to a reduction in GH output. This study examined the GH axis of two mouse models of obesity, the leptin-deficient (ob/ob) mouse and the diet-induced obese (DIO; high-fat fed) mouse. Both models displayed hyperglycemia and hyperinsulinemia with reduced expression of GH as well as reduced expression of pituitary receptors important for GH synthesis and release [GHRH receptor (DIO only) and the ghrelin receptor (ob/ob and DIO)]. These pituitary changes were not accompanied by changes in hypothalamic expression of GHRH or somatostatin; suggesting that alterations in pituitary function may be precipitated in part by direct effects of systemic signals. Of the metabolic and hormonal parameters examined (insulin, glucose, corticosterone, free fatty acids, ghrelin, and IGF-I), only insulin/glucose showed a significant, and negative, correlation with pituitary expression. Pituitaries of DIO mice remained responsive to the acute in vivo actions of insulin, as assessed by phosphorylation of Akt, despite systemic (skeletal muscle and fat) insulin resistance. In addition, treating primary pituitary cell cultures from lean mice with insulin reduced GH release as well as GH, GHRH receptor, and ghrelin receptor mRNA levels compared with vehicle-treated controls, where the magnitude of suppression of pituitary mRNA levels was similar to that observed in the DIO mouse. These results coupled with the fact that the pituitary expresses the insulin receptor at levels comparable to tissues classically considered insulin sensitive, indicates high circulating insulin levels can directly contribute to the suppression of GH synthesis and release in the obese state.