Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1/Akt/Mammalian Target of Rapamycin Pathway in the Prepubertal Female Rat.
Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments. Another experiment assessed in vitro IGF-1 release in response to Mn and assessed signal transduction pathways in the POA/AVPV region after Mn delivery into the third ventricle. Chronic Mn exposure increased (P < .05) basal expressions of mTOR and kisspeptin proteins. Mn increased protein kinase B (Akt) and Ras homolog enriched in brain, both capable of activating mTOR. Central Mn delivery increased expressions of phosphorylated IGF-1 receptor (IGF-1R) (P < .05) and Akt (P < .01) in the POA/AVPV region. The previous central delivery of JB1, an IGF-1R antagonist, blocked Mn-induced expressions of both phosphorylated IGF-1R and Akt. Downstream to Akt, centrally administered Mn increased tuberous sclerosis complex 2 (P < .05), Ras homolog enriched in brain (P < .01), mTOR (P < .05), and kisspeptin (P < .05). Finally, we observed that the early puberty induced by Mn was blocked by the administration of an mTOR inhibitor. These results suggest that Mn acts, at least in part, through the IGF-1/Akt/mTOR pathway to influence prepubertal kisspeptin and LHRH.
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458.
Vinod K
VK
Srivastava
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458.
Jill K
JK
Hiney
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458.
William L
WL
Dees
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011247:Pregnancy; D011629:Puberty, Precocious / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D059648:Kisspeptins; D008345:Manganese; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases