Minireview: Kisspeptin Neurons as Central Processors in the Regulation of Gonadotropin-Releasing Hormone Secretion

Department of Obstetrics and Gynecology, University of Washington Seattle, Seattle, Washington, United States
Endocrinology (Impact Factor: 4.5). 04/2006; 147(3):1154-8. DOI: 10.1210/en.2005-1282
Source: PubMed


The Kiss1 gene encodes a family of peptides called kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in the Arc and up-regulate its expression in the AVPV. Thus, kisspeptin neurons in the Arc may participate in the negative feedback regulation of gonadotropin secretion, whereas kisspeptin neurons in the AVPV may contribute to generating the preovulatory gonadotropin surge in the female. Hypothalamic levels of Kiss1 and GPR54 mRNA increase dramatically at puberty, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Together, these observations demonstrate that kisspeptin-GPR54 signaling in the brain serves as an important conduit for controlling GnRH secretion in the developing and adult animal.

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    • "Kisspeptin-ir neurons in the ARC are targets of estrogen negative feedback, are involved in GnRH/LH pulse generation , and provide tonic and direct stimulatory drive to GnRH neurons (Adachi et al., 2007; Dungan et al., 2006; Kinoshita et al., 2005; Smith, 2008). In agreement, our data show that for C and PF females, when circulating levels of sex steroids declined (OVX), the number of kisspeptin neurons in the ARC increased over Sham levels, and conversely, when circulating levels of E 2 increased (OVX + E 2 H), numbers kisspeptin-ir neurons in the ARC decreased back to Sham levels, reflecting the role of E 2 in negative feedback in the ARC. "
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    ABSTRACT: Background Prenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic–pituitary–gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E2) and progesterone (P4) on the HPG axis. We hypothesized that PAE will have long-term effects on the response of kisspeptin neurons to E2 and P4.Methods Adult female rats (53 to 58 days) from prenatal ad libitum-fed control (C), pair-fed (PF), and alcohol-exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E2 and P4, and terminated under basal conditions. E2 and P4 levels, and the response of kisspeptin-ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E2 signal is conveyed to kisspeptin neurons via estrogen receptor-α (ER-α), we investigated PAE effects on the number of kisspeptin-ir/ER-α-ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons, close contacts between kisspeptin-ir fibers and GnRH-ir cell bodies were examined.ResultsOur data present the novel finding that kisspeptin-ir neurons in the ARC of PAE females show differential responses to E2 and to the combined treatment with E2 and P4 compared with controls: (i) OVX increased the number of kisspeptin-ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E2 replacement restored kisspeptin-ir cell numbers to Sham levels in C and PF females but caused a robust down-regulation of kisspeptin-ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E2 resulted in fewer kisspeptin-ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E2 and P4 markedly decreased the number of kisspeptin-ir neurons, below levels observed following E2 alone, in PF and C females, but had no significant effect in PAE females.Conclusions These data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.
    Alcoholism Clinical and Experimental Research 11/2014; 38(11). DOI:10.1111/acer.12561 · 3.21 Impact Factor
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    • "However, expression of leptin receptor in GnRH neurons is little or zero (10); of course, there are some Kiss neurons in the hypothalamus, which express KiSS-1 mRNA. The KiSS-1 gene encodes 54, 14, 13, and 10 amino-acid peptides, known as kisspeptins (11). Kisspeptins have been detected in various tissues, such as placenta, pancreas, testes, and central nervous system, and are known as a “molecular switch for puberty”. "
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    ABSTRACT: Leptin and adiponectin are the two key metabolic hormones secreted from adipocytes to control food intake and energy expenditure. The action of both hormones in regulation of Gonadotropin Releasing Hormone (GnRH) secretion from the hypothalamus is mediated through Kisspeptins. Kisspeptins are products of KiSS-1 gene. Leptin and adiponectin are modulators of KiSS-1 expression in the hypothalamus. These peptides have also important roles in pancreatic β-cells to control insulin synthesis and secretion and their receptors are detected in Langerhans islets. We hypothesized that leptin and adiponectin might alter KiSS-1 and Kiss Receptor mRNA expression in the islets.
    International Journal of Endocrinology and Metabolism 04/2014; 12(2):e15297. DOI:10.5812/ijem.15297
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    • "Patisaul et al (32) investigated BPA exposure in ovariectomized adult female rats and found no impairment in the signaling from kisspeptin neurons (from anteroventral periventricular (AVPV) to GnRH neurons). Moreover, studies performed on female rats showed that following developmental exposure to BPA, puberty was advanced; however, neither post-pubertal GnRH activation was impaired, nor AVPV or arcuate kisspeptin fiber density was changed (10,31). Recently, Kwon et al (33) examined serum kisspeptin and BPA levels of girls with CPP (n=31) and prepubertal age-matched healthy controls (n=30). "
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    ABSTRACT: Ob­jec­ti­ve: Bisphenol A (BPA) is an industrial chemical, particularly used to harden plastics. BPA is thought to have negative health effects on both laboratory animals and humans. Consider ing the decline in age of onset of puberty noted in recent years, particularly among girls, the importance of BPA as an estrogenic endocrine disruptor has increased. In this study, we aimed to determine urinary BPA levels in girls with idiopathic central precocious puberty (ICPP). Methods: Non-obese girls newly diagnosed with ICPP (n=28, age 4-8 years) constituted the study group. The control group consisted of 25 healthy age-matched girls with no history of ICPP or any other endocrine disorder. Urinary BPA levels were measured by using high-performance liquid chromatography. Results: In the ICPP group, urinary BPA levels were significantly higher compared to the control group [median 8.34 (0.84-67.35) μg/g creatinine and 1.62 (0.3-25.79) μg/g creatinine, respectively (OR=8.68, 95% CI:2.03-32.72, p=0.001)]. There was no marked correlation between urinary BPA levels and body mass index in either group. In the ICPP group, no significant correlations were found between urinary BPA levels and serum luteinizing hormone, follicle-stimulating hormone and estradiol levels. Conclusions: To our knowledge, this is the first study evaluating the urinary BPA levels in Turkish girls with ICPP. Our results indicate that the estrogenic effects of BPA may be an etiologic factor in ICPP.
    Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):16-21. DOI:10.4274/Jcrpe.1220
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