Department of Integrative Biosciences, College of Veterinary Medicine, Texas A and M University College Station, TX 77843-4458, USA.
Neuroscience. 2010 Mar 17;166(2):625-32. doi: 10.1016/j.neuroscience.2009.12.030. Epub 2009 Dec 24.
Kisspeptin, as well as insulin-like growth factor-1 (IGF-1), act centrally to stimulate luteinizing hormone-releasing hormone (LHRH) secretion at puberty. IGF-1 can induce KiSS-1 gene expression as an early pubertal event; however, the signaling pathway mediating this effect is not known. Since alcohol (ALC) blocks IGF-1 induced LHRH release acutely, we assessed whether this drug could affect IGF-1 stimulated prepubertal KiSS-1 gene expression following a binge type of exposure. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 07.30 h. At 09.00 h the ALC and control groups were subdivided where half received either saline or IGF-1 (200 ng) into the third ventricle. A second dose of ALC (1.5, 2 and 3 g/kg) or water was administered at 11.30 h. These regimens produced moderate blood alcohol concentrations of 77, 89 and 117 mg/dl, respectively, over the time course of the experiment. Rats were sacrificed 6 h after the IGF-1 injection and tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were collected. IGF-1 stimulated (P<0.01) KiSS-1 gene expression in the AVPV nucleus at 6 h, but did not affect expression of the kisspeptin receptor, GPR54. While ALC did not alter basal expression of either gene, its dose dependently blocked IGF-1-induced KiSS-1 gene expression in the AVPV nucleus. No changes were observed in the ARC nucleus. Assessment of IGF-1 signaling indicated that the acute administration of IGF-1, ALC, or both did not alter the basal expression of IGF-1 receptor protein. However, IGF-1 stimulated (P<0.05) phosphorylated Akt protein over basal levels, an action blocked by ALC. Our results indicate that the IGF-1 induction of KiSS-1 gene expression is mediated by Akt activation, and that ALC alters this important prepubertal action of IGF-1.
促性腺激素释放激素（LHRH） Kisspeptin 以及胰岛素样生长因子-1（IGF-1）在青春期中枢作用刺激 LHRH 分泌。IGF-1 可诱导 KiSS-1 基因表达作为青春期前的一个事件；然而，介导这种效应的信号通路尚不清楚。由于酒精（ALC）急性阻断 IGF-1 诱导的 LHRH 释放，我们评估这种药物是否可以影响酒精暴露后青春期前的 KiSS-1 基因表达。通过胃管给予未成熟雌性大鼠 ALC（3 g/kg）或水，时间为 07.30 h。在 09.00 h，将 ALC 和对照组分为两组，其中一半分别接受生理盐水或 IGF-1（200 ng）到第三脑室。11.30 h 时给予 ALC（1.5、2 和 3 g/kg）或水的第二剂。这些方案在实验过程中分别产生了 77、89 和 117 mg/dl 的中等血液酒精浓度。在 IGF-1 注射后 6 h 处死大鼠，并收集含有前腹侧室周核（AVPV）和弓状核（ARC）的组织。IGF-1 刺激（P<0.01）6 h 时 AVPV 核中的 KiSS-1 基因表达，但不影响 kisspeptin 受体 GPR54 的表达。虽然 ALC 不改变这两种基因的基础表达，但它剂量依赖性地阻断了 AVPV 核中 IGF-1 诱导的 KiSS-1 基因表达。ARC 核未观察到变化。IGF-1 信号评估表明，IGF-1、ALC 或两者的急性给药均不改变 IGF-1 受体蛋白的基础表达。然而，IGF-1 刺激（P<0.05）磷酸化 Akt 蛋白超过基础水平，该作用被 ALC 阻断。我们的结果表明，IGF-1 诱导 KiSS-1 基因表达是通过 Akt 激活介导的，ALC 改变了 IGF-1 的这一重要青春期前作用。
