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The kisspeptin receptor (GPR54), a member of the G-protein-coupled receptors, plays a central role in regulating reproduction. However, research on GPR54 in allotriploid fish remains limited. In this study, we reported the full-length cDNAs, tissue expression, and localization of gpr54a and gpr54b in allotriploid crucian carp (ACC) and diploid red crucian carp (Carassius auratus red var., RCC). The full-length cDNAs of gpr54a in ACC and RCC were 2224 bp and 2218 bp, respectively. The full-length cDNAs of gpr54b in ACC and RCC were 1413 bp and 1182 bp, respectively. qRT-PCR revealed that ACC gpr54a and RCC gpr54a were highly expressed in the brain but had lower expression in peripheral tissues. Unlike gpr54a, ACC gpr54b and RCC gpr54b were highly expressed in the brain, liver, and muscle. During the breeding season, the expression of gpr54a in ACC was significantly lower than in RCC, but gpr54b had significantly higher expression in ACC than in RCC in the HPG axis. This finding suggested that gpr54a might promote ovarian development, while gpr54b might inhibit ovarian development. During the breeding season, ISH indicated abnormal ovarian development in ACC and found signals of gpr54a and gpr54b in several regions of the brain, pituitary, and ovary of ACC and RCC. These regions of the brain, pituitary, and ovary are associated with the secretion of several hormones related to reproductive regulation. Hence, we hypothesized that the lower expression of gpr54a and higher expression of gpr54b in ACC might be involved in sterility by regulating the secretion of reproductive hormones. This study suggested that gpr54a and gpr54b might function oppositely in regulating reproduction. In conclusion, these findings will aid in further investigating the functions of GPR54 and provide a theoretical basis for studying ACC sterility. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortions (RSA) affect reproductive health and increase the risk of subsequent abortions. to investigate the role of KISS-1/GPR-54 signaling in RSA progression. Villus tissue was collected from Rsa patients, and human trophoblastic HTR-8/SVneo cells were used. KISS-1 and GRP54 levels were detected using RT-qPCR and immunohistochemistry. Western blotting was performed to analyze ZO-1 and ZEB1 levels. cell proliferation was determined via ccK-8 and cell clone formation assays. transwell assays were performed to assess cell migration and invasion abilities. KISS-1 was down-regulated in the villus tissues of RSA patients. KISS-1 overexpression dramatically inhibited trophoblast proliferation, migration, and invasion. Mechanistically, ZEB1 expression was down-regulated, whereas ZO-1 expression was up-regulated, after Kiss-1 overexpression. GPR54 silencing neutralized the effect of KISS-1 in HTR-8/SVneo cells. additionally, Kiss-1 overexpression inactivated the PI3K/AKT signaling pathway through GRP54. the KISS-1/GPR-54 signaling axis regulates RSA progression by regulating the PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety, the most prevalent neuropsychiatric manifestations in Parkinson's disease (PD), negatively impact their quality of life. Aims: To determine whether the chronic nasal administration of kisspeptin-54 (KP-54) could. Alleviate symptoms of anxiety and depression in hemi-Parkinsonian rats. Study Design: Experimental study. Methods: This study included adult Sprague Dawley male rats who were administered either a vehicle (artificial cerebrospinal fluid) or 6-hydroxydopamine (6-OHDA) unilaterally into the medial forebrain bundle. The vehicle, or KP-54 (3 nmol/kg, applied topically to the rhinarium), was administered daily for a seven-day period. The sucrose preference test (SPT), elevated plus maze test (EPMT), and open field test (OFT) were implemented to evaluate depression- and anxiety-like behaviors, respectively, seven days following the lesion surgery. Gamma-aminobutyric acid (GABA) concentrations in the amygdala were quantified using mass spectrometry. Tyrosine hydroxylase in substantia nigra was analyzed using immunohistochemistry. Results: The nasal delivery of KP-54 significantly reduced depressionand anxiety-like behaviors that were induced by 6-OHDA, as indicated by the results of the SPT, OFT, and EPMT. Moreover, it was observed that nasal KP-54 effectively mitigated 6-OHDA-induced motor deficits and the loss of nigral dopaminergic neurons. The nasal administration of KP- 54 augmented the decline in GABA levels in the amygdala induced by 6-OHDA. Furthermore, effective correlations were established between GABA concentrations and behavioral parameters. Conclusion: The nasal delivery of KP-54 could function as a viable therapeutic alternative for treating mood-related disorders in PD. [ABSTRACT FROM AUTHOR]

Different populations of hypothalamic kisspeptin (KISS1) neurons located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC) are thought to generate the sex‐specific patterns of gonadotropin secretion. These neuronal populations integrate gonadal sex steroid feedback with internal and external cues relayed via the actions of neurotransmitters and neuropeptides. The excitatory amino acid neurotransmitter glutamate, the main excitatory neurotransmitter in the brain, plays a role in regulating gonadotropin secretion, at least partially through engaging KISS1 signaling. The expression and function of individual glutamate receptor subtypes in KISS1 neurons, however, are not well characterized. Here, we used GCaMP‐based calcium imaging and patch‐clamp electrophysiology to assess the impact of activating individual ionotropic (iGluR) and group I metabotropic (mGluR) glutamate receptors on KISS1 neuron activity in the mouse RP3V and ARC. Our results indicate that activation of all iGluR subtypes and of group I mGluRs, likely mGluR1, consistently drives activity in the majority of KISS1 neurons within the RP3V and ARC of males and females. Our results also revealed, somewhat unexpectedly, sex‐ and region‐specific differences. Indeed, activating (S)‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) type iGluRs evoked larger responses in female ARCKISS1 neurons than in their male counterparts whereas activating group I mGluRs induced larger responses in RP3VKISS1 neurons than in ARCKISS1 neurons in females. Together, our findings suggest that glutamatergic neurotransmission in KISS1 neurons, and its impact on the activity of these cells, might be sex‐ and region‐dependent in mice. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovarian syndrome (PCOS) is a metabolic disorder, and its pathogenesis is still unclear, but the changes in the hypothalamicpituitary-gonadal (HPG) axis are considered one of the main causes in the development of PCOS. Kisspeptin is a peptide encoded by the KISS gene that regulates the hypothalamus-pituitary-gonadal (HPG), which may be concerned with the pathogenesis of PCO. Aim: To identify the relation between serum Kisspeptin and sex hormones and metabolic parameters among normal and PCO women. Methods: A prospective case-control study was conducted among 64 subjects (32 with PCO and 32 with the control group). The serum Kisspeptin level was measured using enzyme-linked immunosorbent assay (ELISA) and correlated with other hormones such as LH, FSH, DHEA, testosterone, and prolactin. Results: Serum kisspeptin level was significantly higher in the PCOS group when compared to the control group. There was a statistically significant positive correlation between kisspeptin and each of HOMA IR, LH, FSH, DHEA, testosterone, and prolactin. Conclusions: The increase in kisspeptin level may play a role in pathogenesis of PCOS, and may represent a novel link between metabolic and hormonal disturbance in PCOS females since this peptide was correlated with HOMA-IR, LH, FSH, DHEA, testosterone and prolactin. [ABSTRACT FROM AUTHOR]

The peptide hormone kisspeptin attenuates liver steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis in mouse models by signaling via the kisspeptin 1 receptor (KISS1R). However, whether kisspeptin impacts fibrogenesis in the human liver is not known. We investigated the impact of a potent kisspeptin analog (KPA) on fibrogenesis using human precision-cut liver slices (hPCLS) from fibrotic livers from male patients, in human hepatic stellate cells (HSCs), LX-2, and in primary mouse HSCs. In hPCLS, 48 h and 72 h of KPA (3 nM, 100 nM) treatment decreased collagen secretion and lowered the expression of fibrogenic and inflammatory markers. Immunohistochemical studies revealed that KISS1R is expressed and localized to HSCs in MASH/fibrotic livers. In HSCs, KPA treatment reduced transforming growth factor b (TGFβ)-the induced expression of fibrogenic and inflammatory markers, in addition to decreasing TGFβ-induced collagen secretion, cell migration, proliferation, and colony formation. Mechanistically, KISS1R signaling downregulated TGFβ signaling by decreasing SMAD2/3 phosphorylation via the activation of protein phosphatases, PP2A, which dephosphorylates SMAD 2/3. This study revealed for the first time that kisspeptin reverses human hepatic fibrogenesis, thus identifying it as a new therapeutic target to treat hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin‐releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss—often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA. [ABSTRACT FROM AUTHOR]

The neuropeptide kisspeptin and its cognate receptor have been extensively studied in reproductive physiology, with diverse and well‐established functions, including as an upstream regulator of pubertal onset, reproductive hormone secretion, and sexual behavior. Besides classical reproduction, both kisspeptin and its receptor are extensively expressed in bone‐resorbing osteoclasts and bone‐forming osteoblasts, which putatively permits direct bone effects. Accordingly, this sets the scene for recent compelling findings derived from in vitro experiments through to in vivo and clinical studies revealing prominent regulatory interactions for kisspeptin signaling in bone metabolism, as well as certain oncological aspects of bone metabolism. Herein, we comprehensively examine the experimental evidence obtained to date supporting the interaction between kisspeptin and bone. A comprehensive understanding of this emerging facet of kisspeptin biology is fundamental to exploiting the future therapeutic potential of kisspeptin‐based medicines as a novel strategy for treating bone‐related disorders. [ABSTRACT FROM AUTHOR]

Kisspeptins are essential regulators of the reproductive axis, with capacity to potently activate gonadotropin‐releasing hormone neurons, acting also as central conduits for the metabolic regulation of fertility. Recent evidence suggests that kisspeptins per se may also modulate several metabolic parameters, including body weight, food intake or energy expenditure, but their actual roles and site(s) of action remain unclear. We present herein a series of studies addressing the metabolic effects of central and peripheral administration of kisspeptin‐10 (Kp‐10; 1 nmol and 3 nmol daily, respectively) for 11 days in mice of both sexes. To assess direct metabolic actions of Kp‐10 versus those derived indirectly from its capacity to modulate gonadal hormone secretion, kisspeptin effects were tested in adult male and female mice gonadectomized and supplemented with fixed, physiological doses of testosterone or 17β‐estradiol, respectively. Central administration of Kp‐10 decreased food intake in male mice, especially during the dark phase (~50%), which was accompanied by a reduction in total and nocturnal energy expenditure (~16%) and locomotor activity (~70%). In contrast, opposite patterns were detected in female mice, with an increase in total and nocturnal locomotor activity (>65%), despite no changes in food intake or energy expenditure. These changes were independent of body weight, as no differences were detected in mice of both sexes at the end of Kp‐10 treatments. Peripheral administration of Kp‐10 failed to alter any of the metabolic parameters analyzed, except for a decrease in locomotor activity in male mice and a subtle increase in 24 h food intake in female mice, denoting a predominant central role of kisspeptins in the control of energy metabolism. Finally, glucose tolerance and insulin sensitivity were not significantly affected by central or peripheral treatment with Kp‐10. In conclusion, our data reveal a potential role of kisspeptins in the control of key metabolic parameters, including food intake, energy expenditure and locomotor activity, with a preferential action at central level, which is sex steroid‐independent but sexually dimorphic. [ABSTRACT FROM AUTHOR]

Here, we reflect on the long career in neuroendocrinology of a single, highly productive scientist ('Bob' Millar), by analysing his oeuvre of published papers through the lens of citation metrics. We use citation network analysis in a novel manner to identify the specific topics to which his papers have made a particular contribution, allowing us to compare the citations of his papers with those of contemporary papers on the same topic, rather than on the same broad field as generally used to normalise citations. It appears that citation rates are highest for topics on which Bob has published a relatively large number of papers that have become core to a tightly‐knit community of authors that cite each other. This analysis shows that an author's impact depends on the existence of a receptive community that is alert to the potential utility of papers from that author, and which uses, amplifies, extends and qualifies the contents of their papers—activities that entail reciprocal citation between authors. The obvious conclusion is that a scientist's impact depends on the use that his or her contemporaries make of his or her contributions, rather than on the contributions in themselves. [ABSTRACT FROM AUTHOR]

The roles of initially kisspeptin and subsequently neurokinin B pathways in the regulation of human reproduction through the control of GnRH secretion were first identified 20 years ago, as essential for the onset of puberty in both boys and girls. Within that short time we already now have the first licence for clinical use for a neurokinin antagonist in a related indication, for menopausal vasomotor symptoms. Between these two markers of the start and end of the reproductive lifespan, it is clear that these pathways underlie many of the aspects of the hypothalamic regulation of reproduction which had hitherto been enigmatic. In this review, we describe the data currently available from studies designed to elucidate the roles of kisspeptin and neurokinin B in human ovarian function, specifically the regulation of follicle development leading up to ovulation, and in the control of the mid‐cycle GnRH/LH surge that triggers ovulation. These studies, undertaken with only very limited pharmacological tools, provide evidence that the neurokinin B pathway is important in controlling the hypothalamic contribution to the precise gonadotropic drive to the ovary that is necessary for mono‐ovulation, whereas the switch from negative to positive estrogenic feedback results in kisspeptin‐mediated increased GnRH secretion. Potential therapeutic opportunities in conditions characterised by disordered hypothalamic/pituitary function, polycystic ovary syndrome, and functional hypothalamic amenorrhoea, and in the induced LH surge that is a necessary part of IVF treatment are discussed. [ABSTRACT FROM AUTHOR]

Reproductive function in mammals depends on the ability of progesterone (P4) to suppress pulsatile gonadotrophin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in a homeostatic-negative feedback loop. Previous research identified that cells upstream from GnRH neurons expressing the nuclear progesterone receptor (PGR) are required for P4-negative feedback. However, the identity of these cells and the mechanism by which they reduce GnRH/LH pulsatile secretion is unknown. We aimed to address the hypothesis that PGR expressed by a neural population in the arcuate nucleus recently identified as the GnRH pulse generator, cells expressing kisspeptin, neurokinin B, and dynorphin (KNDy cells), mediate P4-negative feedback. To achieve this, we used female mice with the PGR gene conditionally deleted from kisspeptin cells (KPRKO mice) and observed a substantial decrease in the percentage of KNDy neurons coexpressing PGR messenger RNA (mRNA) (11% in KPRKO mice vs 86% in wild-type [WT] mice). However, KPRKO mice did not display changes in the frequency or amplitude of LH pulses in diestrus or estrus, nor in the ability of exogenous P4 to blunt a postcastration increase in LH. Further, mRNA expression of arcuate kisspeptin and dynorphin, which are excitatory and inhibitory to GnRH secretion, respectively, remained unaltered in KPRKO mice compared to WT controls. Together, these findings show that the near-complete loss of PGR signaling from KNDy cells does not affect negative feedback regulation of GnRH pulse generation in mice, suggesting that feedback through this receptor can occur via a small number of KNDy cells or a yet unidentified cell population. [ABSTRACT FROM AUTHOR]

This study examines the role of N-acetylglucosamine kinase (NAGK) in initiating puberty in female mice. We employed real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence to measure NAGK expression in the hypothalamic-pituitary-ovarian axis across various developmental stages: infant, prepuberty, puberty, and adult. We further investigated the impact of Nagk gene knockdown on puberty in female mice. This included assessing the expression of puberty-related genes both in vivo and in vitro , GT1-7 cells proliferation and apoptosis, concentrations of GnRH and Kisspeptin, puberty onset timing, serum levels of progesterone (P 4) and estradiol (E 2), and ovarian morphology. Results revealed that Nagk mRNA is present in the hypothalamus, pituitary, and ovaries throughout different developmental stages in female mice. In the hypothalamus, Nagk mRNA levels were comparable during infant and prepuberty, lowest during puberty, and highest in adult. In the pituitary, Nagk mRNA peaked in adult, with no significant variation between infant, prepuberty, and puberty. In the ovaries, Nagk mRNA levels increased during puberty and peaked in adult. NAGK is predominantly located in the arcuate nucleus (ARC), periventricular nucleus (PeN), dorsomedial hypothalamic nucleus (DMH), paraventricular nucleus (PVN), adenohypophysis, and in the ovarian oocytes, interstitium, and granulosa cells across all developmental stages in female mice. Nagk knockdown in GT1-7 cells decreased the transcriptional level of Gnrh , Kiss1 , Gpr54 , Igf1 and Mapk1 4 mRNA and cell proliferation but increased the level of β-catenin mRNA and cell apoptosis, while reducing GnRH secretion. Following ICV injection, Nagk gene knockdown mice exhibited delayed the timing of vaginal opening (VO) and reduced hypothalamic levels of Gnrh , Kiss1 , Gpr54 , Igf1 , Mapk14 , and β-catenin mRNA. Additionally, serum concentrations of E 2 in Nagk gene knockdown mice were significantly lower compared to the control group. These findings indicate that Nagk regulates the expression of Gnrh and Kiss1 mRNA in GT1-7 cells, affects hypothalamus Gnrh mRNA levels and serum E 2 concentration, and that its knockdown can delay puberty onset in female mice. • NAGK was expressed in the reproductive axis of female mice, with mRNA and protein levels varying by developmental stages. • Knockdown of Nagk in GT1-7 cells can reduce the transcription levels of puberty-related genes. • Knockdown of Nagk in GT1-7 cells can inhibit GnRH secretion and cell proliferation, and promote apoptosis. • Knockdown of Nagk delayed the age at vaginal opening and reduced serum E 2 level in mice. [ABSTRACT FROM AUTHOR]

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected. [ABSTRACT FROM AUTHOR]

This study explored the alteration in kisspeptin and reproductive hormones during different superovulation protocols (SOP) in dromedary camel. The kisspeptin and reproductive hormonal profile, ovarian response, and the quality and quantity of embryos in dromedary camel donors were evaluated. A total of thirty donor camels were divided into two groups: the 5dSOP group, which received diluent containing 400 mg pFSH dissolved in 20 ml and administered two times daily for 5 days at decreasing doses (2.5, 2, 1.5, and 1 ml); and the 3dSOP group, which received diluent containing 400 mg pFSH dissolved in 12 ml and administered two times daily for 3 days at decreasing doses (3 ml, 2 ml, and 1 ml). Ultrasonography was used to monitor the ovarian environment, recording daily follicle count and dimensions and the time taken for follicles to mature. On the sixth day after mating, a corpus luteum (CL) count was conducted. On the 8th day after mating, records of the quantity and quality of embryos collected were kept. Blood samples from the jugular vein were collected at the commencement of the superovulation protocol and at 8:00 a.m. for the following 48 h to measure the concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), kisspeptin (KP), and progesterone (P4). The findings indicated that the 3dSOP yielded superior results compared to the 5dSOP in terms of follicle quantity and size, as well as the quantity of CL and embryos. This improvement was attributed to significantly higher concentrations of reproductive hormones, including FSH, LH, E2, kisspeptin, and P4 (P ≤ 0.05), in the 3dSOP than in the 5dSOP. In conclusion, reducing the duration of superovulation protocols contributed to the proliferation of follicles with improved dimensions and counts, ultimately resulting in a greater quantity of embryos of superior quality. The levels of FSH, LH, E2, KP, and P4 were affected significantly by SOP and time of evaluation. • This is the first experiment to study the alteration in kisspeptin, FSH, LH, E2, and P4 during superovulation protocols in camel. • This study recommended reducing the doses of pFSH to three days instead of five days. • There were significantly higher concentrations of FSH, LH, E2, kisspeptin, and P4 in the 3dSOP than in the 5dSOP. [ABSTRACT FROM AUTHOR]

Introduction: The present meta-analysis aimed to investigate FTO rs9939609 and KISS1 rs4889, rs372790354 gene polymorphisms and its association with PCOS in Asian population. Methods: The studies included in this article were obtained by using online databases. We searched databases such as Scopus, PubMed, Embase, and Web of Science for case–control articles related to FTO and KISS1 gene polymorphism with PCOS. Metagenyo software was used to determine the 95% confidence interval (CI) and odds ratio (OR). Results: A total of 13 articles was included in this meta-analysis for FTO (rs9939609) and KISS1 (rs4889; rs372790354) gene polymorphisms related with PCOS in the Asian population. According to the findings of this study, people with FTO rs9939609 show an association with PCOS risk in dominant model. On contradictory, KISS1 gene polymorphism specifically, rs4889 show an association with PCOS risk in allelic, recessive, and dominant models whereas rs372790354 show an association with PCOS risk in allelic and dominant models. Power analysis was performed and PPI is > 0.04. The sting analysis network for FTO and KISS1 gene estimated 12 nodes and 23 edges. Discussion: The FTO rs9939609 variant exhibits an association with an increased risk of PCOS in the dominant model. KISS1 gene polymorphism, particularly rs4889, shows a significant association with PCOS risk in allelic, recessive, and dominant models. Similarly, KISS1 rs372790354 gene is associated with PCOS risk in both allelic and dominant models. Researches were focused only on the Asian population so; it is imperative to conduct further research across diverse populations. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments? SUMMARY ANSWER Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels. WHAT IS KNOWN ALREADY PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses. LET PCOS-like females also have increased hypothalamic kisspeptin neuronal activation which may drive their hyperactive LH secretion and hyperandrogenemia, but this has not been tested. STUDY DESIGN, SIZE, DURATION Transgenic KissCRE+/hM4Di female mice or littermates Cre− controls were treated with placebo, or chronic LET (50 µg/day) to induce a PCOS-like phenotype, followed by acute (once) or chronic (2 weeks) clozapine- N -oxide (CNO) exposure to chemogenetically inhibit kisspeptin cells (n = 6 to 10 mice/group). PARTICIPANTS/MATERIALS, SETTING, METHODS Key endocrine measures, including in vivo LH pulse secretion patterns and circulating testosterone levels, were assessed before and after selective kisspeptin neuron inhibition and compared between PCOS groups and healthy controls. Alterations in body weights were measured and pituitary and ovarian gene expression was determined by qRT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE Acute targeted inhibition of kisspeptin neurons in PCOS mice successfully lowered the abnormally hyperactive LH pulse secretion (P  < 0.05). Likewise, chronic selective suppression of kisspeptin neuron activity reversed the previously high LH and testosterone levels (P  < 0.05) down to healthy control levels and rescued reproductive gene expression (P  < 0. 05). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Ovarian morphology was not assessed in this study. Additionally, mouse models can offer mechanistic insights into neuroendocrine processes in PCOS-like conditions but may not perfectly mirror PCOS in women. WIDER IMPLICATIONS OF THE FINDINGS These data support the hypothesis that overactive kisspeptin neurons can drive neuroendocrine PCOS-like impairments, and this may occur in PCOS women. Our findings complement recent clinical investigations using NKB receptor antagonists to lower LH in PCOS women and suggest that pharmacological dose-dependent modulation of kisspeptin neuron activity may be a valuable future therapeutic target to clinically treat hyperandrogenism and lower elevated LH in PCOS women. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by NIH grants R01 HD111650, R01 HD090161, R01 HD100580, P50 HD012303, R01 AG078185, and NIH R24 HD102061, and a pilot project award from the British Society for Neuroendocrinology. There are no competing interests. [ABSTRACT FROM AUTHOR]

Kisspeptin, a key neuropeptide derived from the KISS1R gene, is renowned for its critical role in regulating the hypothalamic–pituitary–gonadal axis and reproductive hormone secretion. Beyond its primary function in reproductive biology, emerging research has illuminated its influence in various cancers, mediating significant effects through its interaction with the G protein-coupled receptor, kisspeptin receptor. This interaction has been implicated in modulating cellular processes such as proliferation and metastasis, making it a potential target for therapeutic intervention. Our study initially screened ten kisspeptin-10 analogs through cytotoxic effects of kisspeptin-10 (KP10) and its analogs in several cancer types, including cervical, prostate, breast, and gastric cancers, with a particular focus on cervical cancer, where the most profound effects were observed. Further exploration using kinase array assays revealed that these analogs specifically alter key kinases involved in cancer progression. Migration assays demonstrated a substantial decrease in cell motility, and Bioluminescence Resonance Energy Transfer assays confirmed these analogs' strong interactions with the kisspeptin receptor. Overall, our results indicate that these KP10 analogs not only hinder cervical cancer cell proliferation but also curtail migration through targeted modulation of kinase signaling, suggesting their potential as therapeutic agents in managing cervical cancer progression. This comprehensive approach underscores the therapeutic promise of exploiting kisspeptin signaling in cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-l-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis. [ABSTRACT FROM AUTHOR]

Purpose: To examine the pattern of kisspeptin expression throughout the menstrual cycle in polycystic ovary syndrome (PCOS) patients under the ovulation induction and identify any possible associations with early pregnancy. Materials and methods: A prospective cohort of 80 PCOS women who expressed the desire for fertility was enrolled in this study. All of them received the ovulation induction by using letrozole. Levels of kisspeptin, luteinizing hormone (LH), and estradiol (E2) were measured at three different time points during menstruation. The early pregnancy rate was recorded for the study participants after three ovulation cycles. Results: Kisspeptin levels varied regularly during the menstrual cycle, reaching a peak on the day of hCG injection and decreasing after ovulation. There was no significant correlation between kisspeptin and LH levels. Basal kisspeptin levels decreased after letrozole treatment without a significant difference while LH and E2 levels decreased significantly. PCOS participants who became pregnant early had higher basal kisspeptin levels compared to non-pregnant PCOS patients, which had a significant difference (P = 0.006). And the average basal kisspeptin level in pregnant patients was 2293.0 ± 398.7 pg/ml, with a 95% confidence interval of 1511.5–3074.5 pg/ml. Conclusion: Kisspeptin levels in PCOS women undergoing ovulation induction showed a regular variation, which was similar with the healthy women reported in previous studies. The use of LE may result in PCOS endocrine improvement and fertility achievement. In a certain range, kisspeptin might be a potential predictor for early pregnancy in PCOS patients as people with slightly higher basal kisspeptin levels seemed more likely to be pregnant. [ABSTRACT FROM AUTHOR]

There is a link between metabolism and reproduction as metabolic hormones affect hypothalamus-pituitary-testis (HPT) hormonal functions and vice versa. The aim of the present study was to investigate the effects of negative energy balance on the reproductive system in male goldfish exposed to testosterone (T) and 17β-estradiol (E2). Following 7 days of food deprivation (FD), ANOVA models showed significant FD × sex steroid interactions on sperm quality and circulating sex steroid levels. When FD effects were investigated, 11-ketotestosterone (11-KT) level and sperm motility and velocity decreased in food-deprived goldfish in the control group. In E2-exposed goldfish, FD decreased sperm production in addition to sperm motility and velocity that coincided with an elevation of circulating E2 level. However, FD did not significantly impact sex steroids and sperm quality in T-exposed goldfish. ANOVA models showed non-significant FD × sex steroid interactions for HSI, GSI, circulating luteinizing hormone (Lh) level, and metabolic (preproghrelin, goat and nucb2) and reproductive (kiss1, gpr54 and gnrh3) mRNAs. Furthermore, results showed that FD decreased HSI, and increased Lh levels and testicular preproghrelin and goat mRNAs, while sex steroids increased mid-brain nucb2, kiss1 and gpr54 mRNAs. Together, our results suggest that FD-induced inhibition of androgenesis resulted in diminished sperm quality associated with activation of the testicular ghrelinergic system, and negative feedback of 11-KT increased Lh level. The FD-induced testicular metabolic and hormonal system was impacted in goldfish exposed to sex steroids. However, the negative effects of FD on sperm quality were accelerated in E2-exposed goldfish due to estrogenic activity. This study provides novel information to better understand metabolic-associated reproductive disorders in fish. [ABSTRACT FROM AUTHOR]

Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-β occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress. [ABSTRACT FROM AUTHOR]

Kisspeptin is an essential neuropeptide sitting at the apex of the hypothalamo-pituitary-gonadal (HPG) endocrine axis to regulate gonadotropin-releasing hormone (GnRH) neurons and downstream reproductive hormones. Kisspeptin neurons integrate feedback from sex steroids facilitating regulation of the menstrual cycle and mediate the effects of metabolic stressors on the reproductive axis. In this issue of the JCI, Torres and colleagues describe another pathway for kisspeptin signaling in astrocytes to influence GnRH neuronal output. Astrocytes had kisspeptin receptors that activated canonical intracellular signaling pathways to constrain the magnitude of kisspeptin-induced GnRH neuronal stimulation. Additionally, the appositions between kisspeptin and GnRH neurons were dynamic during the ovarian cycle, with astrocyte kisspeptin signaling proposed as a putative modulator of this neuroplasticity. Importantly, astrocyte kisspeptin signaling also mediated susceptibility to metabolic stressors and the development of obesity-induced hypogonadism, underscoring the physiological and pathological importance of this pathway and revealing the importance of nonneuronal signaling in reproductive health. [ABSTRACT FROM AUTHOR]

In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the pars tuberalis–tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)–related peptide‐3 (RFRP‐3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization. [ABSTRACT FROM AUTHOR]

The pulsatile activity of gonadotropin-releasing hormone neurons (GnRH neurons) is a key factor in the regulation of reproductive hormones. This pulsatility is orchestrated by a network of neurons that release the neurotransmitters kisspeptin, neurokinin B, and dynorphin (KNDy neurons), and produce episodic bursts of activity driving the GnRH neurons. We show in this computational study that the features of coordinated KNDy neuron activity can be explained by a neural network in which connectivity among neurons is modular. That is, a network structure consisting of clusters of highly-connected neurons with sparse coupling among the clusters. This modular structure, with distinct parameters for intracluster and intercluster coupling, also yields predictions for the differential effects on synchronization of changes in the coupling strength within clusters versus between clusters. Author summary: Since the discovery of a small population of hypothalamic neurons that secrete kisspeptin, neurokinin B, and dynorphin (KNDy neurons), there has been interest in their role as a pacemaker for the pulsatile release of key reproductive hormones. A fundamental question is what mechanism coordinates KNDy neuron activity to generate population bursts. Optical imaging of the KNDy network at single-neuron resolution has revealed that individual KNDy neurons participate in many, but not all, population bursts. It has also shown that the order in which the neurons are recruited in each burst could be highly determined in some animals but not in others. We demonstrate here that these observations can be explained by a neural network with a modular structure, and that one benefit of the structure is the ability to differentially modulate the level of synchronization by changes in key coupling parameters. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionsThe hallmarks of Hashimoto’s thyroiditis (HT) include the destruction of thyroid cells by leading to insulin resistance (IR), hypothyroidism, and metabolic abnormalities. Kisspeptin, spexin, and galanin control appetite and body weight (BW) to regulate metabolisms. Here, we sought to determine if galanin, kisspeptin, and spexin are linked to the pathophysiology of HT in euthyroid female individuals.Forty-five women with HT and 45 healthy control women of the same age participated in the current study. The enzyme-linked immunosorbent assay (ELISA) method was used to measure the serum levels of galanin, spexin, and kisspeptin.In comparison to the controls, HT patients had significantly higher levels of kisspeptin (p < 0.01), galanin (p < 0.01), anti-thyroid peroxidase (anti-TPO) (p < 0.001), anti-thyroglobulin (anti-Tg) (p < 0.001), and body mass index (BMI) (p < 0.05). The two groups were comparable in terms of spexin, free triiodothyronine-3 (fT3), fT4, thyroid-stimulating hormone (TSH) levels, and homeostatic model assessment for insulin resistance (HOMA-IR). Galanin and kisspeptin were seen to have a positive correlation (p < 0.01; r = 0.786).Euthyroid women with HT were found to have higher levels of kisspeptin and galanin. These results imply that kisspeptin and galanin may be linked to the pathogenesis of hypothyroidism, and as a result, we believe that these markers may be beneficial in the early detection and treatment of HT patients. [ABSTRACT FROM AUTHOR]

Context: There is mounting evidence implicating kisspeptin signalling in placental development and function. Aims: This study aimed to elucidate kisspeptin's role in trophoblast invasion and migration using three experimental models. Methods: First, we examined the mouse fetus and placenta in a kisspeptin receptor (Kiss1r) knockout (KO) model. Fetal/placental weights and gene expression (quantitative polymerase chain reaction) were assessed. Second, we determined kisspeptin effects on a human trophoblast (BeWo) cell line in vitro. Third, we examined KISS1 and KISS1R gene expression in human placenta from term and pre-term pregnancies. Key results: No difference was found in fetal or placental weight between Kiss1r KO and wildtype mice. However, expression of the trophoblast invasion marker, Mmp2 mRNA, was greater in the placental labyrinth zone of Kiss1r KO mice. BeWo cell models of villus cytotrophoblast and syncytiotrophoblast cells exhibited kisspeptin protein expression, with greater expression in syncytiotrophoblast, consistent with KISS1 mRNA. Kisspeptin treatment inhibited the migratory potential of cytotrophoblast-like cells. Finally, while no difference was seen in KISS1 and KISS1R mRNA between term and pre-term placentas, we saw a difference in the relative expression of each gene pre-term. We also observed a positive correlation between KISS1 expression and maternal body mass index. Conclusions: Our results indicate that kisspeptin may inhibit trophoblast invasion. Implications: Further investigation is required to clarify specific regulatory mechanisms. There is mounting evidence implicating kisspeptin signalling in placental development and function. We sought to elucidate kisspeptin's role in the placenta using three experimental models: a mouse kisspeptin receptor knockout model, culture of human BeWo trophoblast cells, and a human placenta punch biopsy. Our results indicate that kisspeptin may inhibit trophoblast invasion, although further investigation is required to clarify specific regulatory mechanisms. Image by and adapted from M. Arvola and R. Mattsson (). [ABSTRACT FROM AUTHOR]

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obesemice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with anorexigenic POMC neurons, which are affected by obesity, we examined their cross talk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism. [ABSTRACT FROM AUTHOR]

During the last few decades, identifying the physiological pathways involved in appetite regulation has become popular among researchers. Although studying feeding regulation in birds, especially in poultry (for breeding purposes) and ornamental birds (for therapeutic purposes), is extremely important, limited experiments have been conducted on these animal models. Until today, more than 50 neurotransmitters affecting birds' appetite have been identified. In the current study, we overviewed the role of one of the most important neural mediators, neuropeptide Y (NPY), in regulating avian appetite. Based on the findings, the presence of this neuropeptide and its receptors in the key areas of food intake regulation, especially the hypothalamus's arcuate nucleus (ARC), has been proven. Numerous studies on birds have repeatedly shown the hyperphagic effects of NPY. Among the different NPY receptors, type 1, 2, and 5 receptors play the most important role in appetite regulation. It has also been observed that the interaction of NPY with neurotransmitters such as glucagon-like peptide-1 (GLP1), vasotocin, bombesin, opioids, alpha-melanocyte-stimulating hormone (α-MSH), cocaine- and amphetamine-regulated transcript (CART) and gamma aminobutyric acid (GABA) is effective in NPY-induced hyperphagia. In addition, the NPY system is also involved in the effects of various mediators such as adiponectin, neuropeptide W (NPW), phoenixin-14, visfatin, adrenomedullin, spexin, kisspeptin, insulin, and somatostatin on appetite regulation. Finally, NPY seems to be one of the most important appetite-stimulating factors in birds and also plays an undeniable role in the effects of other neurotransmitters on appetite regulation. [ABSTRACT FROM AUTHOR]

The RFamide peptide family is a group of proteins that share a common C-terminal arginine–phenylalanine–amide motif. To date, the family comprises five groups in mammals: neuropeptide FF, LPXRFamides/RFamide-related peptides, prolactin releasing peptide, QRFP, and kisspeptins. Different RFamide peptides have their own cognate receptors and are produced by different cell populations, although they all can also bind to neuropeptide FF receptors with different affinities. RFamide peptides function in the brain as neuropeptides regulating key aspects of homeostasis such as energy balance, reproduction, and cardiovascular function. Furthermore, they are involved in the organization of the stress response including modulation of pain. Considering the interaction between stress and various parameters of homeostasis, the role of RFamide peptides may be critical in the development of stress-related neuropathologies. This review will therefore focus on the role of RFamide peptides as possible key hubs in stress and stress-related psychopathologies. The neurotransmitter coexpression profile of RFamide-producing cells is also discussed, highlighting its potential functional significance. The development of novel pharmaceutical agents for the treatment of stress-related disorders is an ongoing need. Thus, the importance of RFamide research is underlined by the emergence of peptidergic and G-protein coupled receptor-based therapeutic targets in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Reproduction is regulated through the hypothalamic-pituitary-gonadal (HPG) axis, largely via the action of kisspeptin neurons in the hypothalamus. Importantly, Kiss1 neurons have been identified in other brain regions, including the medial amygdala (MeA). Though the MeA is implicated in regulating aspects of both reproductive physiology and behavior, as well as non-reproductive processes, the functional roles of MeA Kiss1 neurons are largely unknown. Additionally, besides their stimulation by estrogen, little is known about how MeA Kiss1 neurons are regulated. Using a RiboTag mouse model in conjunction with RNA-seq, we examined the molecular profile of MeA Kiss1 neurons to identify transcripts that are co-expressed in MeA Kiss1 neurons of female mice and whether these transcripts are modulated by estradiol (E2) treatment. RNA-seq identified >13,800 gene transcripts co-expressed in female MeA Kiss1 neurons, including genes for neuropeptides and receptors implicated in reproduction, metabolism, and other neuroendocrine functions. Of the >13,800 genes co-expressed in MeA Kiss1 neurons, only 45 genes demonstrated significantly different expression levels due to E2 treatment. Gene transcripts such as Kiss1, Gal, and Oxtr increased in response to E2 treatment, while fewer transcripts, such as Esr1 and Cyp26b1, were downregulated by E2. Dual RNAscope and immunohistochemistry was performed to validate co-expression of MeA Kiss1 with Cck and Cartpt. These results are the first to establish a profile of genes actively expressed by MeA Kiss1 neurons, including a subset of genes regulated by E2, which provides a useful foundation for future investigations into the regulation and function of MeA Kiss1 neurons.

The physiology of reproduction has been of interest to researchers for centuries. The purpose of this work is to review the development of our knowledge on the neuroendocrine background of the regulation of ovulation. We first describe the development of the pituitary gland, the structure of the median eminence (ME), the connection between the hypothalamus and the pituitary gland, the ovarian and pituitary hormones involved in ovulation, and the pituitary cell composition. We recall the pioneer physiological and morphological investigations that drove development forward. The description of the supraoptic–paraventricular magnocellular and tuberoinfundibular parvocellular systems and recognizing the role of the hypophysiotropic area were major milestones in understanding the anatomical and physiological basis of reproduction. The discovery of releasing and inhibiting hormones, the significance of pulse and surge generators, the pulsatile secretion of the gonadotropin-releasing hormone (GnRH), and the subsequent pulsatility of luteinizing (LH) and follicle-stimulating hormones (FSH) in the human reproductive physiology were truly transformative. The roles of three critical neuropeptides, kisspeptin (KP), neurokinin B (NKB), and dynorphin (Dy), were also identified. This review also touches on the endocrine background of human infertility and assisted fertilization. [ABSTRACT FROM AUTHOR]

Background: Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an im portant role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. Purpose: To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. Methods: This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of =6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. Results: The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). Conclusion: Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment. [ABSTRACT FROM AUTHOR]

Kisspeptin is a neuropeptide that governs the reproductive axis upstream to GnRH. Present study was undertaken to compare the effect of different doses of kisspeptin on release of luteinizing hormone (LH) in Murrah buffaloes during pre-pubertal period. Twenty four pre-pubertal buffalo heifers were selected and divided into 4 groups (Control, T1, T2 and T3), having 6 animals in each group. Kisspeptin-10 was administered at the dose of 2 µg/kg body weight, 1.5 µg/ kg body weight, 1µg/kg body weight respectively in T1, T2 and T3 group along with administration of equal volume of NSS in control group. Blood sampling was done at every 20 minutes interval beginning with zero minutes up to 2 hours and analyzed for LH concentration. Results indicated that LH concentration was significantly (p<0.05) higher in T1 group. The peak level of LH was recorded at 20 minutes post administration and falls to basal level at 60 minutes post administration. Although increased LH concentration was observed in other treatment groups but it was lower than T1 group. No LH peak or rise in LH level was observed in control group. The result of this study indicates that during the pre-pubertal period, administration of Kisspeptin causes dose dependent increase in LH concentration and peak level was seen at 2 µg/kg body weight of dose. [ABSTRACT FROM AUTHOR]

The trophoblast cells are responsible for the transfer of nutrients between the mother and the foetus and play a major role in placental endocrine function by producing and releasing large amounts of hormones and growth factors. Syncytiotrophoblast cells (STB), formed by the fusion of mononuclear cytotrophoblasts (CTB), constitute the interface between the foetus and the mother and are essential for all of these functions. We performed transcriptome analysis of human placental samples from two control groups—live births (LB), and stillbirths (SB) with a clinically recognised cause—and from our study group, idiopathic stillbirths (iSB). We identified 1172 DEGs in iSB, when comparing with the LB group; however, when we compared iSB with the SB group, only 15 and 12 genes were down- and upregulated in iSB, respectively. An assessment of these DEGs identified 15 commonly downregulated genes in iSB. Among these, several syncytiotrophoblast markers, like genes from the PSG and CSH families, as well as ALPP, KISS1, and CRH, were significantly downregulated in placental samples from iSB. The transcriptome analysis revealed underlying differences at a molecular level involving the syncytiotrophoblast. This suggests that defects in the syncytial layer may underlie unexplained stillbirths, therefore offering insights to improve clinical obstetrics practice. [ABSTRACT FROM AUTHOR]

The presence of Kisspeptin (Kp) and its receptors in the corpus luteum (CL) of buffalo has recently been demonstrated. In this study, we investigated the role of Kp in the modulation of progesterone (P 4) synthesis in vitro. The primary culture of bubaline luteal cells (LCs) was treated with 10, 50, and 100 nM of Kp and Kp antagonist (KpA) alongside a vehicle control. The combined effect of Kp and KpA was assessed at 100 nM concentration. Intracellular response to Kp treatment in the LCs was assessed by examining transcript profiles (LHR, STAR, CYP11A1, HSD3B1 , and ERK1/2) using quantitative polymerase chain reaction (qPCR). In addition, the immunolocalization of ERK1/2 and phosphorylated ERK1/2 (p -ERK1/2) in the LCs was studied using immunocytochemistry. Accumulation of P 4 from the culture supernatant was determined using enzyme-linked immunosorbent assay (ELISA). The results indicated that LCs had a greater p -ERK1/2 expression in the Kp treatment groups. A significant increase in the P 4 concentration was recorded at 50 nM and 100 nM Kp, while KpA did not affect the basal concentration of P 4. However, the addition of KpA to the Kp-treated group at 100 nM concentration suppressed the Kp-induced P 4 accumulation into a concentration similar to the control. There was significant upregulation of ERK1/2 and CYP11A1 expressions in the Kp-treated LCs at 100 nM (18.1 and 37fold, respectively, p < 0.01). However, the addition of KpA to Kp-treated LCs modulated ERK1/2, LHR, STAR, CYP11A1, and HSD3B1 at 100 nM concentration. It can be concluded that Kp at 100 nM stimulated P 4 production, while the addition of KpA suppressed Kp-induced P 4 production in the buffalo LCs culture. Furthermore, an increment in p -ERK1/2 expression in the LCs indicated activation of the Kp signaling pathway was associated with luteal steroidogenesis. • Kisspeptin (Kp) activates ERK1/2 pathway in the bubaline luteal cells in vitro. • Kp upregulated steroidogenic factors and progesterone (P 4) production. • Kp antagonist suppressed Kp-induced P 4 production. [ABSTRACT FROM AUTHOR]

Background: Since kisspeptin (KISS1) in the hypothalamus is affected by the inhibitory effect of dynorphin, it raises questions about the controlled balance of these 2 neuropeptides in women with and without polycystic ovary syndrome (PCOS). Objective: This study compares the expression levels of KISS1, dynorphin, neurokinin-B, leptin, and neuropeptide-Y in women with and without PCOS. Materials and Methods: In this cross-sectional study, the peripheral blood samples of 20 women with PCOS and 20 women without PCOS who referred to Yamin Kencana Clinic, Cipto Mangunkusumo hospital, Jakarta, Indonesia were enrolled from August-December 2022. mRNA relative expression of genes related to the central factors associated with PCOS, such as leptin, neuropeptide-Y, KISS1, tachykinin-3, and prodynorphin (PDYN), in PCOS and non-PCOS populations were examined. Gene quantification was carried out by the quantitative polymerase chain reaction method. Results: The KISS1/PDYN ratio was significantly higher in the PCOS group than in the control group (p = 0.02), and the PDYN was lower in the PCOS group than the control group (p < 0.001). Moreover, the positive correlation between KISS1 and the KISS1/PDYN ratio was significantly stronger in the PCOS group than in the control group (R = 0.93; p <0.001 vs. R = 0.66, p <0.001). Conclusion: Our results suggest that an increased KISS1/PDYN ratio in PCOS women is related to diminished dynorphin expression. Low expression of the gene encoding dynorphin and a high KISS1/PDYN ratio is highly specific to PCOS. [ABSTRACT FROM AUTHOR]

The thin-lipped grey mullet, Liza ramada, a commercially significant fish in Egypt, was studied for its expression patterns along the brain-pituitarygonad axis in female L. ramada during the spawning season of 2022 in both captive and wild habitats. The inspected genes included Kiss2, Gpr54, Gnrh1, and Drd2 genes in the brain and ovary, as well as Lhβ, Fshβ, and Slα genes in the pituitary and ovary. Relative expressions of all studied genes either in the brain, or pituitary, and ovary were higher in ripe females than in immature ones. Captive females had higher Drd2 gene expressions; nevertheless, mature wild females had higher expression values for the other investigated genes that were measured in the brain, or pituitary and ovary. The study found correlations between gene expression patterns in wild and captive females (P< 0.05), suggesting that confinement may affect reproductive physiology. The findings suggest focusing on hormones for artificial fertilization therapies in confined females. [ABSTRACT FROM AUTHOR]

Epigenetic alterations my play a role in the aggressive behavior of Non-Small Cell Lung Cancer (NSCLC). Treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) has been reported to interfere with the proliferative and invasive potential of NSCLC cells. In addition, the DNA methyltransferase inhibitor azacytidine (AZA, vidaza) can modulate the levels of the metastasis suppressor KiSS-1. Thus, since cisplatin is still clinically available for NSCLC therapy, the aim of this study was to evaluate drug combinations between cisplatin and SAHA as well as AZA using cisplatin-sensitive H460 and -resistant H460/Pt NSCLC cells in relation to KiSS-1 modulation. An analysis of drug interaction according to the Combination-Index values indicated a more marked synergistic effect when the exposure to SAHA or AZA preceded cisplatin treatment with respect to a simultaneous schedule. A modulation of proteins involved in apoptosis (p53, Bax) was found in both sensitive and resistant cells, and compared to the treatment with epigenetic agents alone, the combination of cisplatin and SAHA or AZA increased apoptosis induction. The epigenetic treatments, both as single agents and in combination, increased the release of KiSS-1. Finally, the exposure of cisplatin-sensitive and -resistant cells to the kisspeptin KP10 enhanced cisplatin induced cell death. The efficacy of the combination of SAHA and cisplatin was tested in vivo after subcutaneous inoculum of parental and resistant cells in immunodeficient mice. A significant tumor volume inhibition was found when mice bearing advanced tumors were treated with the combination of SAHA and cisplatin according to the best schedule identified in cellular studies. These results, together with the available literature, support that epigenetic drugs are amenable for the combination treatment of NSCLC, including patients bearing cisplatin-resistant tumors. [ABSTRACT FROM AUTHOR]

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To understand better the role that kisspeptin plays in regulating seasonal and estrous cycle changes in the mare, this study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the equine hypothalamus. Hypothalami were collected from mares during the non-breeding season, vernal transition and various stages of the breeding season. Fluorescent immunohistochemistry was used to label the neuropeptides of interest. GnRH cells were observed primarily in the arcuate nucleus (ARC), while very few labeled cells were identified in the pre-optic area (POA). Kisspeptin cells were identified primarily in the ARC, with a small number of cells observed dorsal to the ARC, surrounding the third ventricle (3V). The mean number of kisspeptin cells varied between animals and typically showed no pattern associated with season or stage of estrous cycle, but a seasonal difference was identified in the ARC population. Small numbers of RFRP-3 cells were observed in the ARC, ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). The mean number of RFRP-3 cells appeared higher in pre-ovulatory animals compared to all other stages. The percentage of GnRH cell bodies with kisspeptin appositions did not change with season or stage of estrous cycle. The percentage of kisspeptin cells receiving inputs from RFRP-3 fibers did not vary with season or stage of estrous cycle. These interactions suggest the possibility of the presence of an ultra-short loop feedback system between these three peptides. The changes in RFRP-3 neurons suggest the possibility of a role in the regulation of reproduction in the horse, but it is unlikely to be as a gonadotropin inhibitory factor. • Study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the hypothalamus of the mare. • Compared numbers across the estrous cycle and between seasons. [ABSTRACT FROM AUTHOR]

Background: Infertility affects about 15% of couples during reproductive age and male factor infertility accounts for half of these cases. This study aimed to evaluate the expression of leptin, KISS1, leptin receptor, and HOTAIR genes in blood and semen samples of individuals diagnosed with oligospermia in comparison to healthy controls. Methods: In the current investigation, we studied 36 semen and 30 blood samples from fertile oligospermic men as well as the same number of healthy controls. RNA was extracted and cDNA was synthesized. Real-time polymerase chain reaction (PCR) was conducted to assess the gene expression levels. Statistical analysis was performed using Graph Pad Prism software. The results were reported as mean±SEM and any P< 0.05 were considered statistically significant. Results: A significant increase in the expression of the leptin gene in infertile males, particularly in semen samples (P< 0.001) was found when compared to the healthy controls. On the other hand, significant decrease in the expression of the KISS1 (P< 0.0001) and HOTAIR (P< 0.001) genes, particularly in semen samples were found when compared to the controls. As it was shown, the expression of leptin receptor had no significant effects on male infertility. Additionally, there may be a potential correlation between the expression of HOTAIR and the leptin and KISS1 genes, with a negative correlation observed between HOTAIR and leptin, and a positive correlation between HOTAIR and KISS1 in both blood and semen samples. However, further investigations are necessary to establish the statistical significance of these correlations. Conclusion: According to the results, leptin, KISS1, and HOTAIR genes seem to be affected in oligospermia, however, further studies with higher sample sizes are necessary. [ABSTRACT FROM AUTHOR]

Kisspeptin is a peptide that plays a crucial function in the regulation of puberty initiation, by sexual immaturity and slowed puberty advancement. Infertility is a result of hyperprolactinemia, which inhibits the pulsatile release of GnRH from the brain and lowers the pulsatile production of LH from the pituitary. In type 1 diabetes, also known as autoimmune diabetes, pancreatic cells die off and the body cannot produce enough insulin, leading to high blood sugar levels. Obese people are more likely to suffer from hyperinsulinemia, hyperlipidemia, hyperleptinemia, chronic inflammation, menstrual abnormalities, pregnancy troubles, and infertility. So, this study aims to know the reproductive status of women by estimating kisspeptin and other hormones. The study was conducted on 92 women, ages (20-40) years, Samples were collected from the AL-Sader Teaching Hospital, Maysan for Child and Birth Hospital, the specialized Centre for Diabetes and Endocrinology and some private clinics and centres, the period June 2022 to February of 2023. The women were divided equally into four groups: control group (with regular menstrual cycles), hyperprolactinemia group (hyper serum prolactin), obesity group (have a BMI over 30 kg.m–2), and type 1 diabetes group. The results showed the values of kisspeptin did not differ significantly (P>0.05) in all groups, values of GnRH in hyperprolactinemia, obesity and type 1 DM groups increased significantly (P≤0.05) compared with the control group, Prolactin, estradiol and progesterone in the hyperprolactinemia group increased significantly (P≤0.05) in comparison with other groups. According to the above results, we conclude that high levels of prolactin, also obesity and type 1 DM influence the reproductive hormones in women. [ABSTRACT FROM AUTHOR]

Kisspeptins (KPs) are proteins that were first recognized to have antimetastatic action. Later, the critical role of this peptide in the regulation of reproduction was proved. In recent years, evidence has been accumulated supporting a role for KPs in regulating metabolic processes in a sexual dimorphic manner. It has been proposed that KPs regulate metabolism both indirectly via gonadal hormones and/or directly via the kisspeptin receptor in the brain, brown adipose tissue, and pancreas. The aim of the review is to provide both experimental and clinical evidence indicating that KPs are peptides linking metabolism and reproduction. We propose that KPs could be used as a potential target to treat both metabolic and reproductive abnormalities. Thus, we focus on the consequences of disruptions in KPs and their receptors in metabolic conditions such as diabetes, undernutrition, obesity, and reproductive disorders (hypogonadotropic hypogonadism and polycystic ovary syndrome). Data from both animal models and human subjects indicate that alterations in KPs in the case of metabolic imbalance lead also to disruptions in reproductive functions. Changes both in the hypothalamic and peripheral KP systems in animal models of the aforementioned disorders are discussed. Finally, an overview of current clinical studies involving KP in fertility and metabolism show fewer studies on metabolism (15%) and only one to date on both. Presented data indicate a dynamic and emerging field of KP studies as possible therapeutic targets in treatments of both reproductive and metabolic dysfunctions. [ABSTRACT FROM AUTHOR]

The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C‐terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5‐(3‐aminopropylcarbamoyl)‐2‐[[tert‐butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine‐containing analogue revealed that the group is not compatible with receptor activation. [ABSTRACT FROM AUTHOR]

The mechanisms regulating puberty still remain elusive, as do the underlying causes for sex differences in puberty onset (girls before boys) and pubertal disorders. Neuroendocrine puberty onset is signified by increased pulsatile GnRH secretion, yet how and when various upstream reproductive neural circuits change developmentally to govern this process is poorly understood. We previously reported day-by-day peri-pubertal increases (Kiss1, Tac2) or decreases (Rfrp) in hypothalamic gene expression of female mice, with several brain mRNA changes preceding external pubertal markers. However, similar pubertal measures in males were not previously reported. Here, to identify possible neural sex differences underlying sex differences in puberty onset, we analyzed peri-pubertal males and directly compared them with female littermates. Kiss1 expression in male mice increased over the peri-pubertal period in both the AVPV and ARC nuclei but with lower levels than in females at several ages. Likewise, Tac2 expression in the male ARC increased between juvenile and older peri-pubertal stages but with levels lower than females at most ages. By contrast, both DMN Rfrp expressionand Rfrp neuronal activation strongly decreased in males between juvenile and peri-pubertal stages, but with similar levels as females. Neither ARC KNDy neuronal activation nor Kiss1r expression in GnRH neurons differed between males and females or changed with age. These findings delineate several peri-pubertal changes in neural populations in developing males, with notable sex differences in kisspeptin and NKB neuron developmental patterns. Whether these peri-pubertal hypothalamic sex differences underlie sex differences in puberty onset deserves future investigation.

Objective: In this study, it is aimed to investigate the relationship between serum adiponectin and kisspeptin levels and insulin resistance in patients with PCOS. Methods: 144 patients diagnosed with PCOS in a tertiary center, were included in the study. At the first visit, the height and weight measurements were recorded and menstrual functions were questioned. After ultrasonographic evaluation and hormonal assessment, patients were divided into groups according to insulin resistance (IR), then were compared in terms of hormonal parameters. Results: Weight and BMI were significantly higher in the insulin-resistant group (p=0.018, p=0.012). Mean fasting glucose, fasting insulin levels and HOMA indexes of the insulin-re)sistant group were significantly higher than the non-resistant group, respectively (p<0.001). LH/FSH ratios were significantly lower in the IR+ group (1.33 vs 1.58, p<0.05). No significant difference was observed between the groups in terms of adiponectin and kisspeptin levels, but the mean kisspeptin level in the IR- group was higher than the IR+ group (32.72 vs 19.36, p=0.067). Adiponectin and kisspeptin were both found to have a very weak positive relation)ship with FSH (r=0.169 and 0.171). Conclusion: Adiponectin is known to decrease in obesity and type 2 diabetes, but does not show the difference in insulin-resistant PCOS patients. Kisspeptin, which is a hypotha)lamic peptide and associated with increased LH levels in patients with PCOS, was found to be lower in the IR+ group. In order to clarify the role of kisspeptin and adiponectin in the mechanisms of PCOS and insulin resistance, it is needed to be examined in a larger sample with BMI-matched healthy controls. [ABSTRACT FROM AUTHOR]

Pain, an unpleasant feeling resulting from physical or psychological damage, manifests in various diseases such as migraine, fibromyalgia, rheumatoid arthritis, back pain, and neuropathy, disrupting the physiology of the body system. Prolonged pain can detrimentally affect other body tissues, leading to disorders by interfering with hormone secretion. Several studies show that pain can damage the reproductive process. Within the hypothalamus, a population of kisspeptin, neurokinin B, and dynorphin (KNDy) neurons plays an important role in regulating the reproductive axis. This study aims to investigate the effect of pain on hypothalamic neuron activity and its subsequent implications on the reproductive pathway. [ABSTRACT FROM AUTHOR]

The inactive ovaries of cattle caused a significant economic loss, so the current study is intended to recover and enhance the fertility of dairy cattle suffering from anestrus by kisspeptin-10. Forty Holstein Friesian cows, aged 3.5-6.8 years with inactive ovaries for 60-70 days of postpartum, were distributed randomly into four equal groups. The control (C) group administered 5 mL intramuscularly (I.M) of normal saline, Gn group administered 0.5 mg/animal I.M of GnRH. K1 and K2 were administered with 6 μg/kg BW I.M and 12 μg/kg BW I.M of kisspeptin-10, respectively. After heat signs were detected, artificial insemination was performed. Blood samples were collected at 0, 2, 6, 24, and 72 hours post-hormonal injection to estimate fertility hormones, and fecundity features were demonstrated after hormonal treatment and after twelve months. The current results noted a significant (p<0.05) increment in estradiol, FSH, and LH in K1 and K2 cows compared to Gn and C at 6-24 h post hormonal treatment, while progesterone showed a significant (p<0.05) drop in K1, Gn, and K2 in comparison with C. Also, the calving and fertility rates were significantly higher (p<0.05) in K2 and K1 compared with Gn and C after hormonal treatment and after one year. The kisspeptin-10 injection improved the fertility of anestrus cows by enhancing the reproductive hormonal profile and fertility traits for long-term effects and without requiring a second kisspeptin-10 injection in Holstein Friesian cows; therefore, administration of kisspeptin-10 can be regarded as an alternative application of using some hormones like GnRH. [ABSTRACT FROM AUTHOR]

Purpose: Currently, several genetic variants in ERα gene (rs2234693 and rs9340799), ERβ gene (rs1256049 and rs4986938), KISS1 gene (rs4889, rs1132506 and rs5780218), LIN28B gene (rs314263, rs314276 and rs314280), and MKRN3 gene (rs2239669) have been repeatedly explored for their contribution to precocious puberty (PP) susceptibility. However, the results remain conflicting rather than conclusive. We here performed a meta‐analysis to identify the real susceptibility genetic variants for PP. Methods: After screening by inclusion criteria, 20 related studies were finally included in this meta‐analysis. The odds ratios and 95% confidence intervals were calculated to assess the strength of association. Sensitive analysis, publication bias, and trial sequential analysis (TSA) were performed to evaluate the stability and reliability of results. Results: Rs2234693, rs9340799, and rs1256049 were significantly associated with PP susceptibility (p < 0.0084). Stratified analysis according to ethnicity showed that rs2234693 and rs9340799 were significantly associated with PP susceptibility in Asian and Chinese populations. Stratified analysis according to PP subtype showed that rs2234693 and rs9340799 were significantly associated with idiopathic central PP susceptibility in Asian and Chinese populations (p < 0.0084). The results of publication bias, sensitivity analysis, and TSA provided solid evidence for the association between these three variants and PP susceptibility. Conclusions: Rs2234693 and rs9340799 in ERα gene and rs1256049 in ERβ gene may serve as susceptive factors for PP development. The present finding should be confirmed in replication studies and reinforced in functional studies, which will ultimately improve the feasibility of the application of these three PP‐susceptible loci in clinical practice. [ABSTRACT FROM AUTHOR]