Role of Kisspeptin in Puberty and Reproduction

2011, Vol. 6 No. 2, Article 87

Pratheesh M.D*, Radhika Syam¹, C. Harish², R. Anoopraj² and Justin Davis¹

*Veterinary Physiology and Climatology Division
¹Veterinary Bacteriology Division
²Veterinary Pathology Division
Indian Veterinary Research Institute, Izatnagar, Bareilly-UP

*Corresponding Author; e-mail address: [email protected]

ABSTRACT

Kisspeptin (a product of the KiSS1 gene) and its receptor (GPR54) have emerged as key players in the regulation of reproduction in animals. Studies reported 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. Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Kisspeptin signaling in the brain has been implicated in generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology etc.

KEY WORDS

Kisspeptin, GPR54, KiSS 1gene, puberty, AVPV nucleus, arcuate nucleus.

INTRODUCTION

The kisspeptins (KP) were originally identified as a product of a metastasis suppressor gene, KiSS-1, in malignant melanomas by Lee et al (1996). Kisspeptins are endogenous ligands for a G-protein-coupled receptor named GPR54 (KiSS-1R). Proteolytic processing of the full-length 145 amino acid kisspeptin protein results in shorter fragments of the carboxyl -terminus region of the molecule with 54 (KP-54), 14 (KP14), 13 (KP-13) or 10 (KP-10) amino acids (Kotani et al. 2001). Initially, the largest cleavage product, KP-54 was identified for its ability to suppress the metastatic potential of malignant melanoma cells (Lee & Welch 1997) and it was therefore termed ‘metastin’.
As it was discovered in Hershey (Pennsylvania), the gene was named after Hershey’s famous chocolate “Kisses”. However, the nomenclature also has a scientific grounding as the inclusion of ‘SS’ in the name also indicates that the gene is a suppressor sequence. The term ‘kisspeptins’ is now widely employed to collectively describe this family of peptides that show an Arg–Phe–NH2 motif at the C-terminus, characteristic of the extensive RF-amide peptide superfamily (Roa et al. 2008).

TISSUE DISTRIBUTION AND LOCALIZATION.

Distribution of kisspeptin has been best described in rodents, where expression of both receptor (GPR54) and ligand (KiSS1) are the highest in placenta, with additional wide distribution throughout the central nervous system (the highest levels in hypothalamus and pituitary but also in cerebellum, cortex and brainstem) (Kotani et al. 2001). There are also some reports of variable expression in adipose tissue, pancreas, liver, small intestine, peripheral blood lymphocytes, testes, lymph nodes, and in human aorta, coronary artery and umbilical vein. (Muir et al. 2001, Hauge-Evans et al. 2006, Mead et al. 2007). In situ hybridization assays in mice have revealed that kisspeptin neurons (i.e. those that express Kiss1 mRNA) are most numerous in the arcuate nucleus (Arc), but significant numbers are also seen in periventricular nucleus (PeN) and the anteroventral periventricular nucleus (AVPV) (Smith et al.,2005). Although both sexes express Kiss1 mRNA in all five areas, expression in the AVPV is sexually dimorphic, where the expression of Kiss1 mRNA is much greater in females, the region directly implicated in the generation of pre-ovulatory GnRH/LH surge in female. This finding is not surprising considering that the AVPV in females is larger by volume and contains more neurons than the AVPV of males (Bleiber et al.,1982).

KISSPEPETIN REALLY TRIGGERS PUBERTY?

Does puberty begins with a ‘kiss’?. In mammals, activation of GnRH neurons is the key vent gating the onset of puberty; however, the mechanisms that trigger GnRH secretion at puberty remain one of the enigmas of modern science . Intriguingly, sexual maturation is impaired in animals with targeted deletions or spontaneous mutations in the GPR54 gene (Funes et al. 2003) suggesting that kisspeptin -GPR54 signaling is essential for pubertal maturation. Moreover, exogenous kisspeptin administered to prepubertal rodents and monkeys initiates various aspects of precocious puberty such as LH secretion or vaginal opening (Matsui et al.2004; Shahab et al.2005). Similarly, neural KiSS-1 gene expression increases in both male and female rats, mice and monkeys from pre- to post-puberty (Han et al. 2005); however, the specific KiSS-1 population(s) (ARC versus AVPV) that changes with puberty is equivocal and might reflect species-specific mechanisms that differ between primates and rodents (Plant et al.2005).Regardless, changes in the activity of KiSS-1 neurons appear to represent a seminal and perhaps common event in the timing of puberty in many species. Collectively, the findings indicate that hypothalamic-derived kisspeptin–GPR54–GnRH signaling is intimately involved in the mechanism(s) that initiate puberty, but precisely how this signaling is triggered remains a mystery.
In a study conducted by Smith and co-workers in 2005 found that Kisspepttin induced release of sex steroids from gonads have positive feed back effect on the KiSS I neuron expression in AVPV nucleus whereas negative feedback effect on Arcuate nucleus neurons. The suppression of kisspeptin activity by sex steroids in the Arc appears to be mediated by estrogen receptors (ER) in the female and both ER and androgen receptors in the male. Nearly all kisspeptin cells in the AVPV of the female and male rodent express ER. These observations suggest that kisspeptin neurons in the ARC and AVPV of both the male and female provide tonic drive to GnRH-neuronal activity, which is modulated by the negative/positive feedback effects of gonadal steroids (testosterone in the male and estradiol in the female).

THEORETICAL MODEL FOR THE FUNCTION OF KISSPEPTIN.

The enhancement of endogenous KiSS-1 tone in the hypothalamus takes place during pubertal attainment and such activation of GPR54 is apparently sufficient to trigger the neuroendocrine events leading to the onset of puberty. Kisspeptin stimulates the neuroendocrine reproductive axis, and sex steroids differentially regulate the expression of KiSS-1 mRNA in different nuclei within the forebrain. Kisspeptin released by neurons in the AVPV and Arc stimulates GnRH release, which induces the release of LH and FSH. The gonads respond to gonadotropins by secreting sex steroids, which then feed back to regulate the activity of kisspeptin neurons, inhibiting KiSS-1 expression in the Arc and inducing its expression in the AVPV (see Figure-1). The inductive effect of sex steroids on KiSS-1 expression in the AVPV may contribute to the preovulatory LH surge in females (and possibly T-mediated sex behavior in the male).

ROLE OF KISSPEPTIN IN VARIOUS PHYSIOLOGICAL PROCESSES IN ANIMALS.

1. Estrous cycle:
The stimulation of the gonadotrophin axis by the kisspeptin, suggested possible involvement in the positive feedback loop between oestrogen, GnRH and LH and regulation of the estrous cycle. In extracts of the whole hypothalamus, kisspeptin mRNA expression changed as a function of the oestrous cycle with kisspeptin expression being at its lowest at proestrus and it is highest at dioestrus (Navarro et al. 2004). However, it was later shown that expression of kisspeptin is at its highest in the AVPV at proestrus, when it is also at its lowest in the Arc (Smith et al. 2005a). Additionally, in the ovary maximum levels of kisspeptin were identified at proestrus, with levels remaining low throughout the rest of the cycle with the exception of a transient increase at dioestrus (Castellano et al. 2006a). No changes in GPR54 were detected, Suggesting that expression of kisspeptin / GPR54 in the AVPV mediates the process of the GnRH surge at proestrus and ovulation, whereas kisspeptin neurons in the Arc are likely to play a role in the negative feedback regulation of GnRH/gonadotrophin secretion (Smith et al. 2005a)
2. Pregnancy and Placenta:
Circulating kisspeptin levels are low in males and nonpregnant females (<2 pmol/L) but dramatically increase in pregnancy (Horikoshi et al. 2003).Circulating kisspeptin levels fell again 5 days post delivery to comparable concentrations prior to pregnancy, implicating a placental source of the peptide. Kisspeptin has a prime location at the foeto-maternal interface, being abundant in the syncytiotrophoblast of the both normal human placenta (Bilban et al. 2004) and in molar pregnancies (Janneau et al. 2002). The outer syncytiotrophoblasts lie adjacent to blood vessels allowing easy passage of kisspeptin into the maternal blood . Intriguingly, levels of expression of both KISS1 and KISS1R mRNA are higher in first trimester placentae than in term placentae (Bilban et al. 2004).
3. Ageing:
Aging takes a toll on the reproductive system, most obviously in females .This becomes reflected in disrupted cycles and eventually constant estrus (or diestrus) in rodents. This does not appear to be due to a defect in the ARC, but a serious defect in the AVPV, because preliminary data indicate that declining expression of kisspeptin in the AVPV occurs in middle-aged female rats, reducing the stimulatory drive of kisspeptin to GnRH neurons and delaying the estradiol mediated GnRH/LH surge (Downs et al.2009).
4. Lactation:
Lactating rats have reduced expression of KiSS1 mRNA in the ARC region and GPR54 mRNA expression in the AVPV (Yamada et al.2007), providing a possible mechanism to explain the reduction of LH secretion during lactation. The suckling stimulus appears to be responsible for the suppression of KiSS1 mRNA expression in the ARC .γ-Aminobutyric acid and/or catecholamines may be candidates for the inhibitory inputs to the kisspeptin neurons. Suckling-induced reduction in kisspeptin and GPR54 represents a mechanism whereby estrous cycles is shut down during lactation.
5. Metabolic Regulation:
Evidence suggests that the activity of KiSS1 neurons is influenced by body weight, nutrition, metabolism, and hormonal signals . As noted previously, significant fraction of KiSS1 neurons (40%) in the ARC express the leptin receptor, Ob-Rb (Smith et al.,2006 ). Leptin is a satiety factor, which is produced by white adipocytes and regulates KiSS1 neurons in the arcuate nucleus. In a state of malnutrition (or fasting), which reduce gonadotropin secretion as well as the expression of KiSS1,exogenous kisspeptin administration can reinstate reproductive function (Roa et al.2008a). However, it is conceivable that the apparent rescue of the reproductive axis associated with poor nutrition or diabetes that occurs with kisspeptin simply reflects its ability to activate GnRH neurons downstream of the mechanisms that are impaired in these altered metabolic states. Collectively, these findings point to a potentially important role of KiSS1 neurons in regulation of reproduction by metabolic factors.
6. Kisspeptin in Seasonal reproduction:
In several species, reproduction is controlled photoperiodically (Revel et al. 2006). The role of kisspeptin in timing of puberty made them likely modulators of the photoperiodic control. In Syrian hamsters, where reproduction is promoted by long days and inhibited by short days, kisspeptin were significantly lower in short-day animals, an effect reliant on melatonin signalling, as pineal gland ablation prevented the downregulation. In the Arc of ewe, brain kisspeptin mRNA expression was lower during anoestrus, due to a non-steroid-dependent seasonal effect, further suggesting a role for kisspeptin in control of seasonal changes in reproductive function (Smith et al. 2008).

CONCLUSIONS

The pairing of the Kisspeptin with the GPR54 receptor has received growing attention since the description of the receptor as a molecular switch for puberty. Mechanisms underlying the role of GPR54 in puberty are the focus of the majority of emerging reports into this receptor system. A significant body of evidence across several species now suggests that KiSS-1 activation is a critical point in the commencement of puberty, although further investigation is required to fully characterize the interaction between Kisspeptin and the GnRH cascade.

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FIGURES

Fig 1 : A schematic representation of our current understanding of KiSS-1 signaling in the forebrain of the mouse. Kisspeptin stimulates GnRH secretion by a direct effect on GnRH neurons, most of which express the kisspeptin receptor, GPR54. Neurons that express KiSS-1 mRNA reside in the AVPV and the ARC (arcuate). KiSS-1 neurons in the ARC appear to be involved in the negative feedback regulation of GnRH/LH by sex steroids. The expression of KiSS-1 mRNA in the arcuate is inhibited by estradiol (E), progesterone (P), and testosterone (T). These same hormones induce KiSS-1 mRNA expression in the AVPV, where KiSS-1 neurons are thought to be involved in the positive feedback regulation of GnRH/LH. Source: [Gottsch et al. 2004]

kisspeptin