PMID- 27309941
OWN - NLM
STAT- MEDLINE
DCOM- 20170531
LR  - 20211204
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 157
IP  - 8
DP  - 2016 Aug
TI  - Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1/Akt/Mammalian Target of 
      Rapamycin Pathway in the Prepubertal Female Rat.
PG  - 3233-41
LID - 10.1210/en.2016-1090 [doi]
AB  - 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.
FAU - Srivastava, Vinod K
AU  - Srivastava VK
AD  - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, 
      Texas A&M University, College Station, Texas 77843-4458.
FAU - Hiney, Jill K
AU  - Hiney JK
AD  - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, 
      Texas A&M University, College Station, Texas 77843-4458.
FAU - Dees, William L
AU  - Dees WL
AD  - Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, 
      Texas A&M University, College Station, Texas 77843-4458.
LA  - eng
GR  - R01 ES013143/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20160616
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Kisspeptins)
RN  - 42Z2K6ZL8P (Manganese)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Female
MH  - Insulin-Like Growth Factor I/*metabolism
MH  - Kisspeptins/*metabolism
MH  - Manganese/*pharmacology
MH  - Oncogene Protein v-akt/*metabolism
MH  - Pregnancy
MH  - Puberty, Precocious/chemically induced/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Sexual Maturation/drug effects/physiology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4967113
EDAT- 2016/06/17 06:00
MHDA- 2017/06/01 06:00
PMCR- 2017/08/01
CRDT- 2016/06/17 06:00
PHST- 2016/06/17 06:00 [entrez]
PHST- 2016/06/17 06:00 [pubmed]
PHST- 2017/06/01 06:00 [medline]
PHST- 2017/08/01 00:00 [pmc-release]
AID - EN-16-1090 [pii]
AID - 10.1210/en.2016-1090 [doi]
PST - ppublish
SO  - Endocrinology. 2016 Aug;157(8):3233-41. doi: 10.1210/en.2016-1090. Epub 2016 Jun 
      16.