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Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.

ABSTRACT: 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.

SUBMITTER: Hiney JK

PROVIDER: S-EPMC2823990 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.

Hiney J K JK Srivastava V K VK Les Dees W W

Neuroscience 20091224 2

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 ...[more]

PMID: 20034543

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Project description:Alcohol (ALC) diminishes gonadotropin-releasing hormone (GnRH) secretion and delays puberty. Glial transforming growth factor ?1 (TGF?1) plays a role in glial-neuronal communications facilitating prepubertal GnRH secretion. We assessed the effects of acute ALC administration on TGF?1-induced GnRH gene expression in the brain preoptic area (POA) and release of the peptide from the medial basal hypothalamus (MBH). Furthermore, we assessed actions and interactions of TGF?1 and ALC on an adhesion/signaling gene family involved in glial-neuronal communications.Prepubertal female rats were administered ALC or water via gastric gavage at 7:30 am. At 9:00 am, saline or TGF?1 (100 ng/3 ?l) was administered into the third ventricle. At 3:00 pm, the POA was removed and frozen for gene expression analysis and repeated for protein assessments. In another experiment, the MBH was removed from ALC-free rats. After equilibration, tissues were incubated in Locke's medium only or medium containing TGF?1 with or without 50 mM ALC for measurement of GnRH peptide released in vitro.TGF?1 induced GnRH gene expression in the POA, and this effect was blocked by ALC. We also described the presence and responsiveness of the TGF?1 receptor in the POA and showed that acute ALC exposure not only altered the TGF?1-induced increase in TGF?-R1 protein expression but also the activation of receptor-associated proteins, Smad2 and Smad3, key downstream components of the TGF?1 signaling pathway. Assessment of an adhesion/signaling family consisting of glial receptor protein tyrosine phosphatase beta and neuronal contactin-associated protein-1 (Caspr1) and contactin showed that the neuronal components were induced by TGF?1 and that ALC blocked these effects. Finally, TGF?1 was shown to induce release of the GnRH peptide in vitro, an action that was blocked by ALC.We have demonstrated glial-derived TGF?1 induces GnRH gene expression in the POA and stimulates release of the peptide from the MBH, actions necessary for driving the pubertal process. Importantly, ALC acted at both brain regions to block stimulatory effects of TGF?1. Furthermore, ALC altered neuronal components of an adhesion/signaling family previously shown to be expressed on GnRH neurons and implicated in glial-GnRH neuronal communications. These results further demonstrate detrimental effects of ALC at puberty.

Dataset Information

Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.

Publications

Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.

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