Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor
Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor
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DOI：
10.1073/pnas.0305930101
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发表时间：
2004-03-30
影响因子：
11.1
通讯作者：
Smith, RG
中科院分区：
文献类型：
--
作者：
Sun, YX;Wang, P;Smith, RG
生长激素促分泌素受体(GHSR)的合成激动剂使老年人GH释放的脉动模式恢复活力，并增加肥胖者的瘦而不是脂肪质量。对过度表达GHSR的细胞系中的组织提取物进行筛选，从而鉴定出一种名为Ghrelin的天然激动剂。矛盾的是，这种荷尔蒙与肥胖有关。然而，还没有直接证明GHSR是一种生理上相关的Ghrelin受体。此外，ghrelin的结构与用于表达-克隆GHSR的合成激动剂(MK-0677)有显著不同。为了说明GHSR是否介导了Ghrelin对生长激素释放和食欲的刺激作用，我们培育了GHSR缺失的小鼠。与野生型小鼠相比，用Ghrelin急性处理GHSR缺失小鼠既不刺激GH释放，也不刺激食物摄取，表明GHSR是一种生物学上相关的Ghrelin受体。然而，GHSR-neill小鼠并不是矮小的；它们的食欲和身体成分与野生型小鼠相当。此外，与Ghrelin调节瘦素和胰岛素分泌的说法相反，禁食导致的血清瘦素和胰岛素水平的变化在野生型和空白小鼠中是相同的。与野生型小鼠相比，成年GHSR缺失型小鼠的血清胰岛素样生长因子1水平和体重略有降低，这与ghrelin作为生长激素脉动性放大器的特性以及其在建立维持合成代谢的胰岛素样生长因子1设置点方面的推测作用一致。我们的结果表明，长期使用胃促生长素拮抗剂治疗对生长或食欲影响不大。
Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. in contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-nuill mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fasting-induced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.