{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:03:16Z","timestamp":1788238996869,"version":"build-2803163510"},"reference-count":49,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:p>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 &amp;lt; .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 &amp;lt; .05) and Akt (P &amp;lt; .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 &amp;lt; .05), Ras homolog enriched in brain (P &amp;lt; .01), mTOR (P &amp;lt; .05), and kisspeptin (P &amp;lt; .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.<\/jats:p>","DOI":"10.1210\/en.2016-1090","type":"journal-article","created":{"date-parts":[[2016,6,16]],"date-time":"2016-06-16T18:08:36Z","timestamp":1466100516000},"page":"3233-3241","source":"Crossref","is-referenced-by-count":28,"title":["Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1\/Akt\/Mammalian Target of Rapamycin Pathway in the Prepubertal Female Rat"],"prefix":"10.1210","volume":"157","author":[{"given":"Vinod K.","family":"Srivastava","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K.","family":"Hiney","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L.","family":"Dees","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2016,6,16]]},"reference":[{"key":"2020071612024163100_B1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0021-9258(18)72630-6","article-title":"Studies on manganese deficiency in the rat","volume":"143","author":"Boyer","year":"1942","journal-title":"J Biol Chem"},{"key":"2020071612024163100_B2","first-page":"281","article-title":"Manganese deficiency in the rabbit","volume":"4","author":"Smith","year":"1944","journal-title":"Arch Biochem 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