Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.
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.
Hiney
J K
JK
Department of Integrative Biosciences, College of Veterinary Medicine, Texas A and M University College Station, TX 77843-4458, USA. jhiney@cvm.tamu.edu
Srivastava
V K
VK
Les Dees
W
W
D000818:Animals; D015153:Blotting, Western; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D059648:Kisspeptins; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
C491406:Kiss1 protein, rat; D059648:Kisspeptins; D011506:Proteins; D012333:RNA, Messenger; D000431:Ethanol; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt