Role Of Kisspeptin Research Articles

Exploring AOP's and biomarkers of carcinogenesis in rats using laser dissection targeted (LDT) microarray profiling and pathways analysis

To avoid breeding during unsuitable environmental or physiological circumstances, the reproductive axis adjusts its output in response to fluctuating internal and external conditions. The ability of the reproductive system to alter its activity appropriately in response to these cues has been well established. However, the means by which reproductively relevant cues are interpreted, integrated and relayed to the reproductive axis remain less well specified. The neuropeptide kisspeptin has been shown to be a potent positive stimulator of the hypothalamo–pituitary–gonadal (HPG) axis, suggesting a possible neural locus for the interpretation/integration of these cues. Because a failure to inhibit reproduction during winter would be maladaptive for short-lived female rodents, female Siberian hamsters (Phodopus sungorus) housed in long and short days were examined. In long “summer” photoperiods, kisspeptin is highly expressed in the anteroventral periventricular nucleus (AVPV), with low expression in the arcuate nucleus (Arc). A striking reversal in this pattern is observed in animals held in short, “winter” photoperiods, with negligible kisspeptin expression in the AVPV and marked staining in the Arc. Although all studies to date suggest that both populations act to stimulate the reproductive axis, these contrasting expression patterns of AVPV and Arc kisspeptin point to disparate roles for these two cell populations. Additionally, we found that the stimulatory actions of exogenous kisspeptin are blocked by acyline, a gonadotropin-releasing hormone (GnRH) receptor antagonist, suggesting an action of kisspeptin on the GnRH system rather than pituitary gonadotropes. Finally, females held in short day lengths exhibit a reduced response to exogenous kisspeptin treatment relative to long-day animals. Together, these findings indicate a role for kisspeptin in the AVPV and Arc as an upstream integration center for reproductively relevant stimuli and point to a dual mechanism of reproductive inhibition in which kisspeptin expression is reduced concomitant with reduced sensitivity of the HPG axis to this peptide.

Kisspeptin-13 enhances memory and mitigates memory impairment induced by Aβ1–42 in mice novel object and object location recognition tasks

Kisspeptin (KP), the endogenous ligand of GPR54, is a recently discovered neuropeptide shown to be involved in regulating reproductive system, anxiety-related behavior, locomotion, food intake, and suppression of metastasis across a range of cancers. KP is transcribed within the hippocampus, and GPR54 has been found in the amygdala and hippocampus, suggesting that KP might be involved in mediating learning and memory. However, the role of KP in cognition was largely unclear. Here, we investigated the role of KP-13, one of the endogenous active isoforms, in memory processes, and determined whether KP-13 could mitigate memory impairment induced by Aβ1–42 in mice, using novel object recognition (NOR) and object location recognition (OLR) tasks. Intracerebroventricular (i.c.v.) infusion of KP-13 (2μg) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. The memory-improving effects of KP-13 could be blocked by the GPR54 receptor antagonist, kisspeptin-234 (234), and GnRH receptors antagonist, Cetrorelix, suggesting pharmacological specificity. Then the memory-enhancing effects were also presented after infusion of KP-13 into the hippocampus. Moreover, we found that i.c.v. injection of KP-13 was able to reverse the memory impairment induced by Aβ1–42, which was inhibited by 234. To sum up, the results of our work indicate that KP-13 could facilitate memory formation and prolong memory retention through activation of the GPR54 and GnRH receptors, and suppress memory-impairing effect of Aβ1–42 through activation of the GPR54, suggesting that KP-13 may be a potential drug for enhancing memory and treating Alzheimer’s disease.

Augmentation of Metastin/Kisspeptin mRNA Expression by the Proestrous Luteinizing Hormone Surge in Granulosa Cells of Rats: Implications for Luteinization.

Variations in mRNA levels and sources of metastin/kisspeptin, neurokinin B (NKB), dynorphin, and kisspeptin receptor GPR54 were examined in the ovaries of cycling rats. Kisspeptin and dynorphin mRNAs dramatically increased at 2000 h of the proestrous day. NKB mRNA also increased, but the peak was delayed by 6 h. GPR54 mRNA declined inversely with kisspeptin. Whole-ovary expressions of kisspeptin and dynorphin mRNAs, but not of NKB mRNA, were augmented by the administration of human chorionic gonadotropin (hCG). By means of laser-capture microdissection, kisspeptin mRNA was shown mostly in follicles at 2000 h of proestrus, whereas NKB and dynorphin were expressed mainly in interstitial tissues. GPR54 mRNA was detected equally in follicles, corpora lutea, and interstitial tissues. The hCG stimulated the follicular expression of kisspeptin and interstitial tissue expression of dynorphin mRNA. In primary cultures of granulosa cells prepared from equine chorionic gonadotropin-pretreated immature rats, hCG stimulated the expression of kisspeptin, dynorphin, and NKB mRNAs. Distortion of the corpus luteum and surrounding tissue borders was sometimes seen after intra-ovarian bursa administration of kisspeptin antagonist p234 for 3 days from proestrus. Progesterone production stimulated by hCG in granulosa cell culture was suppressed by p234. These data demonstrate that significant amounts of kisspeptin are synthesized in granulosa cells and dynorphin in interstitial tissues, in response to the proestrous luteinizing hormone surge, whereas granulosa cells also contain dynorphin and NKB, suggesting at least a role for kisspeptin in the luteinization of granulosa cells.

Kisspeptin signaling in the amygdala modulates reproductive hormone secretion.

Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain. KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala. To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist. Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency. We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility. Our data suggest that kisspeptin is a ‘master regulator’ of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.

A review of recent developments in buffalo reproduction - a review.

The buffalo is an important livestock resource in several countries of South Asia and the Mediterranean regions. However, reproductive efficiency is compromised due to known problems of biological and management origins, such as lack of animal selection and poor nutrition. Under optimal conditions puberty is attained at 15 to 18 months in river buffalo, 21 to 24 months in swamp buffalo and is influenced by genotype, nutrition, management and climate. However, under field conditions these values deteriorate up to a significant extant. To improve reproductive efficiency, several protocols of oestrus and ovulation synchronization have been adopted from their use in commercial cattle production. These protocols yield encouraging pregnancy rates of (30% to 50%), which are comparable to those achieved in buffaloes bred at natural oestrus. The use of sexed semen in buffalo heifers also showed promising pregnancy rates (50%) when compared with conventional non-sexed semen. Assisted reproductive technologies have been transferred and adapted to buffalo but the efficiency of these technologies are low. However, these latest technologies offer the opportunity to accelerate the genetic gain in the buffalo industry after improving the technology and reducing its cost. Most buffaloes are kept under the small holder farming system in developing countries. Hence, future research should focus on simple, adoptable and impact- oriented approaches which identify the factors determining low fertility and oestrus behaviour in this species. Furthermore, role of kisspeptin needs to be explored in buffalo.

Kisspeptin regulates tuberoinfundibular dopaminergic neurones and prolactin secretion in an oestradiol-dependent manner in male and female rats.

Prolactin (PRL) secretion is inhibited by hypothalamic dopamine. Kisspeptin controls luteinising hormone (LH) secretion and is also involved in PRL regulation. We further investigated the effect of kisspeptin-10 (Kp-10) on the activity of tuberoinfundibular dopaminergic (TIDA) neurones and the role of oestradiol (E2 ) in this mechanism. Female and male rats were injected with i.c.v. Kp-10 and evaluated for PRL release and the activity of dopamine terminals in the median eminence (ME) and neurointermediate lobe of the pituitary (NIL). Kp-10 at the doses of 0.6 and 3nmol increased plasma PRL and decreased 4-dihydroxyphenylacetic acid (DOPAC) levels in the ME and NIL of ovariectomised (OVX), E2 -treated rats but had no effect in OVX. In gonad-intact males, 3nmol Kp-10 increased PRL secretion and decreased DOPAC levels in the ME but not in the NIL. Castrated males treated with either testosterone or E2 also displayed increased PRL secretion and reduced ME DOPAC in response to Kp-10, whereas castrated rats receiving oil or dihydrotestosterone were unresponsive. By contrast, the LH response to Kp-10 was not E2 -dependent in either females or males. Additionally, immunohistochemical double-labelling demonstrated that TIDA neurones of male rats contain oestrogen receptor (ER)-α, with a higher proportion of neurones expressing ERα than in dioestrous females. The dopaminergic neurones of periventricular hypothalamic nucleus displayed much lower ERα expression. Thus, TIDA neurones express ERα in male and female rats, and kisspeptin increases PRL secretion through inhibition of TIDA neurones in an E2 -dependent manner in both sexes. These findings provide new evidence about the role of kisspeptin in the regulation of dopamine and PRL.

Mutation of kisspeptin 1 gene in children with precocious puberty in isfahan city.

Background:Considering the role of kisspeptin (KISS) in the process of puberty, this study aimed to determine the mutation of KISS1 gene among a group of patients with idiopathic central precocious puberty (ICPP).Methods:In this case control study, a group of children with diagnosed ICPP and a group of healthy children were selected. Genomic DNA was extracted from peripheral blood of selected population. After proving the quality and quantity of extracted DNA samples by nano-drop instrument, PCR was performed using 3 set of primers to amplify all coding exons and flanking intron region of Kiss1 gene.Results:In this study, 33 patients with idiopathic PP and 30 control age and sex matched children were studied. Genetic analysis indicated that there was not any polymorphism or mutation in studied participants of the control group. Among patients with ICPP, 4 single nucleotide polymorphisms within the promoter and coding regions of KISS1 gene were determined in 9 patients (5 boys and 4 girls). Among them, the c.-148 T > A was novel variant.Conclusions:The results of the current study identified one novel polymorphism and three reported polymorphism in KISS gene among patients with ICPP. It is recommended to design further studies for analysis other genes related to ICPP in accordance with more complementary biochemical evaluations is recommended also.

Kisspeptins in physiology and pathology of sex development - new diagnostic and therapeutic approaches

The article is dedicated to mechanisms of the human reproductive system development mechanisms. The evolution of the opinions on that processes was analysed. The review of modern knowledge of molecular and genetic causes of sex development, new mechanisms of gonadal axis regulation and role of kisspeptins in pubertat start and sexual differentiation of the brain are presented. The new actual directions of scientific research as well as the applications of kisspeptin drugs for new therapeutic approaches, treatment of hormone-dependent diseases and abnormalities of sex developmentare are observed.

The Role of Kisspeptin in the Onset of Puberty and in the Ovulatory Mechanism: A Mini-review

The onset of puberty has been a fascinating topic for reproductive endocrinologists for decades; however, its underlying physiological mechanisms have remained elusive until recently. The discovery and understanding of the effects exerted by the peptide hormone kisspeptin have shed light on this research area. This review is aimed to discuss the functions of kisspeptin, with special focus on its role in the onset of puberty and in the ovulatory mechanism. The points under discussion are (1) the characteristics of kisspeptin and its receptor, (2) the relevance of this hormone and its interaction with leptin in the onset of puberty, (3) the role of kisspeptin in the ovulatory mechanism based on its differential expression at hypothalamic nuclei, which is modulated by sex steroid hormones, and (4) the clinical relevance of kisspeptin and its antagonists in new therapeutic strategies for the treatment of various reproductive pathologies. All of this explains the revolution that kisspeptin has caused among researchers working in the field of gynecological endocrinology and reproductive biology.

The role of kisspeptin for defeminization and masculinization of sexual behaviors in rats

The role of kisspeptin for defeminization and masculinization of sexual behaviors in rats

The role of kisspeptin in immune tolerance formation during pregnancy.

The role of kisspeptin in immune tolerance formation during pregnancy.

Kisspeptin Effect on Endothelial Monocyte Activating Polypeptide II (EMAP-II)-Associated Lymphocyte Cell Death and Metastases in Colorectal Cancer Patients

Kisspeptin is an antimetastatic agent in some cancers that has also been associated with lymphoid cell apoptosis, a phenomenon favoring metastases. Our aim was to determine the association of kisspeptin with lymphocyte apoptosis and the presence of metastases in colorectal cancer patients. Blood was drawn from 69 colon cancer patients and 20 healthy volunteers. Tissue specimens from healthy and pathological tissue were immunohistochemically analyzed for kisspeptin and endothelial monocyte activating polypeptide II (EMAP-II) expression. Blood EMAP-II and soluble Fas ligand (sFasL) levels were examined by an enzyme-linked immunosorbent assay method. The kisspeptin and EMAP-II expression and secretion levels in the DLD-1 and HT-29 colon cancer cell lines were examined by quantitative real-time polymerase chain reaction, Western analysis and enzyme-linked immunosorbent assay, whereas lymphocyte viability was assessed by flow cytometry. The effect of kisspeptin on the viability of colon cancer cells was examined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. Exogenous, synthetic and naturally produced, kisspeptin induces through the G-protein-coupled receptor 54 (GPR54; also known as the kisspeptin receptor) the EMAP-II expression and secretion in colon cancer cell lines, inducing in vitro lymphocyte apoptosis, as verified by the use of an anti-EMAP-II antibody. These results were reversed with the use of kisspeptin inhibitors and by kisspeptin-silencing experiments. Tumor kisspeptin expression was associated with the tumor EMAP-II expression (p < 0.001). Elevated kisspeptin and EMAP-II expression in colon cancer tissues was associated with lack of metastases (p < 0.001) in colon cancer patients. These data indicate the antimetastatic effect of tumor-elevated kisspeptin in colon cancer patients that may be mediated by the effect of kisspeptin on EMAP-II expression in colon cancer tumors in patients with normal serum EMAP-II levels. These findings provide new insight into the role of kisspeptin in the context of metastases in colon cancer patients.

Kisspeptins (KiSS-1): Essential Players in Suppressing Tumor Metastasis

Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers.

Kiss1 and Kiss1 receptor expression in the rhesus monkey testis: a possible local regulator of testicular function

Abstract

THE TIMING OF PUBERTY: WELL-KNOWN AND NEW ISSUES

Puberty is an important developmental milestone. It can be considered as a complex sequence of biological events leading to progressive maturation of sexual characteristics ultimately leading to attainment of full reproductive capacity. The decline in age at puberty in the general population has been paralleled by an increase in the number of girls referred for evaluation of precocious puberty (PP). The recent pubertal trends have resulted in a concomitant lowering of the lower limit of normality of the pubertal onset. However, evidence suggests that age at the gonadotropin and sex steroid surges have not changed. Thus, it looks as if an increasing proportion of contemporary early pubertal girls may experience isolated gonadotropinindependent thelarche rather than central PP, which may not be discernible on pubertal examination alone. Thus, the population-based limits of normality srapid progressive PP as well as intracranial and other underlying pathology. The initiation of mammalian puberty requires an increased pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This increase is brought about by changes in transsynaptic and glial-neuronal communication. Coordination of these cellular interactions likely requires the participation of sets of genes hierarchically arranged within functionally connected networks. The role of kisspeptins in the control of GnRH neurons and the transmission of the regulatory actions of key signals, such as sex steroids, metabolic hormones and environmental cues, has been recently studied, point out that the Kiss1 system is an indispensable player of the brain sexual differentiation during early periods of maturation and the timing of puberty onset.

Kisspeptin Neurons from Mice to Men: Similarities and Differences

The discovery that kisspeptin was critical for normal fertility in humans ushered in a new chapter in our understanding of the control of GnRH secretion. In this paper, we will review recent data on the similarities and differences across several mammalian species in the role of kisspeptin in reproductive neuroendocrinology. In all mammals examined to date, there is strong evidence that kisspeptin plays a key role in the onset of puberty and is necessary for both tonic and surge secretion of GnRH in adults, although kisspeptin-independent systems are also apparent in these studies. Similarly, two groups of kisspeptin neurons, one in the arcuate nucleus (ARC) and the other more rostrally, have been identified in all mammals, although the latter is concentrated in a limited area in rodents and more scattered in other species. Estrogen has divergent actions on kisspeptin expression in these two regions across these species, stimulating it the latter and inhibiting expression in the former. There is also strong evidence that the rostral population participates in the GnRH surge, whereas the ARC population contributes to steroid-negative feedback. There may be species differences in the role of these two populations in puberty, with the ARC cells important in rats, sheep, and monkeys, whereas both have been implicated in mice. ARC kisspeptin neurons also appear to participate in the GnRH surge in sheep and guinea pigs, whereas the data on this possibility in rodents are contradictory. Similarly, both populations are sexually dimorphic in sheep and humans, whereas most data in rodents indicate that this occurs only in the rostral population. The functional consequences of these species differences remain to be fully elucidated but are likely to have significance for understanding normal neuroendocrine control of reproduction as well as for use of kisspeptin agonists/antagonists as a therapeutic tool.

The role of Kisspeptin in sexual development

Activation of gonadotrophic hormone neuronstion and downstream reproductive hormones (luteinizing hormone and follicle stimulating hormone) secretion is the key event representing the onset of puberty.Hypothalamic pituitary gonad axis varies among gender,season and the stage of development.A number of hormones are involved in the control of hypothalamic pituitary gonad axis.Kisspeptins are potent secretagogues for gonadotrophic hormone,and the KISS1 gene is a target for regulation by gonadal steroids,metabolic factors,photoperiod,and season.This review focuses on Kisspeptin in the regulation of sexual development. Key words: Kisspeptin; G-protein-coupled receptor 54; Gonadotrophic hormone; Hypothalamic pituitarygonad axis

Kisspeptins and the control of gonadotrophin secretion

Kisspeptins, the peptide products of the KiSS-1 gene, bind to the G protein coupled receptor 54 (GPR54). Since 2003, research has revealed the important role of kisspeptins in initiating puberty, timing puberty and regulating fertility in adulthood. Specific mutations in GPR54 gene cause either delayed/absent puberty or precocious puberty. The KiSS-1/GPR54 system stimulates the gonadotrophin releasing hormone (GnRH) neurons and is involved in the feedback regulation of the HPG axis by gonadal steroids. Different hypothalamic nuclei are involved in negative (arcuate nucleus; ARC) and positive (anteroventral periventricular nucleus; AVPV) feedback in mice. Continuous administration of kisspeptins down-regulates the HPG axis. During pregnancy, kisspeptins are secreted from the placenta in large amounts and are responsible for the physiological invasion of primary human trophoblast. Kisspeptins have been administered to normal male and female individuals as well as to women with hypothalamic secondary amenorrhoea. In all cases, gonadotrophin secretion was potently stimulated. Kisspeptin antagonists have been synthesized to successfully suppress GnRH and gonadotrophin release. These agonists and antagonists appear as valuable new tools for manipulating the HPG axis and are promising drugs for future treatment. The scope of this review highlights the role of kisspeptins in regulating gonadotrophin secretion and explores their possible therapeutic use.

The Role of Kisspeptin and RFamide‐Related Peptide‐3 Neurones in the Circadian‐Timed Preovulatory Luteinising Hormone Surge

Many aspects of female reproduction often require intricate timing, ranging from the temporal regulation of reproductive hormone secretion to the precise timing of sexual behaviour. In particular, in rodents and other species, ovulation is triggered by a surge in pituitary luteinising hormone (LH) secretion that is governed by a complex interaction between circadian signals arising in the hypothalamus and ovarian-derived oestradiol signals acting on multiple brain circuitries. These circadian and hormonal pathways converge to stimulate a precisely-timed surge in gonadotropin-releasing hormone (GnRH) release (i.e. positive-feedback), thereby triggering the preovulatory LH surge. Reflecting its control by afferent circadian signals, the preovulatory LH surge occurs at a specific time of day, typically late afternoon in nocturnal rodents. Although the specific mechanisms mediating the hormonal and circadian regulation of GnRH/LH release have remained poorly understood, recent findings now suggest that oestradiol and circadian signals govern specific reproductive neuropeptide circuits in the hypothalamus, including the newly-identified kisspeptin and RFamide-related peptide (RFRP)-3 neuronal populations. Neurones producing kisspeptin, the protein product of the Kiss1 gene, and RFRP-3 have been shown to provide excitatory and inhibitory input to GnRH neurones, respectively, and are also influenced by sex steroid and circadian signals. In the present review, we integrate classic and recent findings to form a new working model for the neuroendocrine regulation of the circadian-timed preovulatory LH surge in rodents. This model proposes kisspeptin and RFRP-3 neuronal populations as key nodal points for integrating and transducing circadian and hormonal signals to the reproductive axis, thereby governing the precisely-timed LH surge.

Teasing apart socially‐induced infertility in non‐reproductive female Damaraland mole‐rats, Fukomys damarensis (Rodentia: Bathyergidae)

The Damaraland mole-rat is a subterranean mammal exhibiting extreme reproductive skew with a single reproductive female in each colony responsible for procreation. Non-reproductive female colony members are physiologically suppressed while in the colony, exhibiting reduced concentrations of plasma luteinizing hormone (LH) and a decreased response of the pituitary, as measured by the release of bioactive LH, to an exogenous dose of gonadotrophin releasing hormone (GnRH). Removal of the reproductive female from the colony results in an elevation of LH and an enhanced response of the pituitary to a GnRH challenge in non-reproductive females comparable to reproductive females, implying control of reproduction in these individuals by the reproductive female. The Damaraland mole-rat is an ideal model for investigating the physiological and behavioral mechanisms that regulate the hypothalamo-pituitary-gonadal axis. In contrast, we know less about the control of reproduction at the level of the hypothalamus. The immunohistochemistry of the GnRH system of both reproductive and non-reproductive female Damaraland mole-rats has revealed no significant differences with respect to morphology, distribution or numbers of immunoreactive GnRH perikarya. We examined whether the endogenous opioid peptide beta-endorphin was responsible for the inhibition of the release of the GnRH from the neurons indirectly by measuring LH concentrations in these non-reproductive females following single, hourly and 8 hourly injections of the opioid antagonist naloxone. The results imply that the endogenous opioid peptide, beta-endorphin, is not responsible for the inhibition of GnRH release from the perikarya in non-reproductive females. Preliminary data examining the circulating levels of cortisol also do not support a role for circulating glucocorticoids. The possible role of kisspeptin is discussed.