Search

Kisspeptin is a major regulator of gonadotropin secretion in pigs. Previously, CRISPR/Cas9 knockout of KISS1 was used to develop a mosaic parental line of pigs to generate offspring that would not need castration due to loss of kisspeptin. The current goal was to characterize growth and reproductive development of F1 pigs from this parental line. Body weights, gonadotropin concentrations and gonadal development were measured from birth through development (boars to 220 days of age, n = 42; gilts to 160 days of age, n = 36). Testosterone, skatole, and androstenone were also measured in boars. Blood samples were collected by jugular venipuncture for quantification of serum hormones, gonadal tissues were collected for gross morphology and histology, and a fat biopsy was collected (boars) for skatole and androstenone analysis. Body weight did not differ with genotype. There were no differences between KISS1+/+ and heterozygote KISS1+/- animals for most parameters measured. Gonadotropin concentrations were reduced in KISS1-/- boars and gilts compared with KISS1+/+ and KISS1+/- animals (P < 0.05). Concentrations of testosterone in serum and both androstenone and skatole in adipose were less in KISS1-/- boars than in KISS1+/+ and KISS1+/- boars (P < 0.05). Hypogonadism was present in all KISS1-/- gilts and boars. These data indicate that knocking out KISS1 causes hypogonadotropic hypogonadism but does not negatively affect growth in pigs. Only one KISS1 allele is needed for normal gonadotropin secretion and gonadal development, and accumulation of compounds in adipose leading to boar taint., (Published by Oxford University Press on behalf of Society for the Study of Reproduction 2024.)

Temperature is a preeminent factor in the regulation of fish reproduction and hinders gonadal development beyond a specific threshold. To comprehend the molecular mechanism responsible for reproductive suppression at different temperature, expression of the genes encoding kisspeptin (kiss2), gonadotropin-releasing hormone (gnrh1) and their receptors (gpr54, gnrh1r) in the brain, and the gonadotropin (GTH) subunits (fshb and lhb) in the pituitary were studied in juvenile Nile tilapia (Oreochromis niloticus) along with gonadal histology. Fish were acclimatized to three distinct temperatures, including 31 °C, 34 °C and 37 °C for 14 days. The mRNA levels of kiss2, gpr54, gnrh1, and gnrh1r were significantly decreased at 37 °C compared to 31 °C and 34 °C in the both sexes. In parallel, the expression level of fshb in the both sexes and lhb in the female were significantly lower at 37 °C in the pituitary. Histologically, the gonads of both sexes had normal growth of gametes at control temperature (31 °C), whereas the spermatogenesis and oocyte maturation were slowed down and atretic oocytes were found in the ovary at 37 °C acclimation temperature. Taken together, the results imply that elevated temperature beyond the specific threshold may have a negative impact on reproduction by suppressing the gene expressions of kisspeptin/GnRH1/GTH system and eventually restrains normal growth and maturation of gametes in the both sexes of Nile tilapia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Puberty is the critical developmental transition to reproductive capability driven by the activation of gonadotropin-releasing hormone (GnRH) neurons. The complex neural mechanisms underlying pubertal activation of GnRH secretion still remain unknown, yet likely include kisspeptin neurons. However, kisspeptin neurons reside in several hypothalamic areas and the specific kisspeptin population timing pubertal onset remains undetermined. To investigate this, we strategically capitalized on the differential ontological expression of the Kiss1 gene in different hypothalamic nuclei to selectively ablate just arcuate kisspeptin neurons (aka KNDy neurons) during the early juvenile period, well before puberty, while sparing RP3V kisspeptin neurons. Both male and female transgenic mice with a majority of their KNDy neurons ablated (KNDy ABL ) by diphtheria toxin treatment in juvenile life demonstrated significantly delayed puberty onset and lower peripubertal LH secretion than controls. In adulthood, KNDy ABL mice demonstrated normal in vivo LH pulse frequency with lower basal and peak LH levels, suggesting that only a small subset of KNDy neurons is sufficient for normal GnRH pulse timing but more KNDy cells are needed to secrete normal LH concentrations. Unlike prior KNDy ablation studies in rats, there was no alteration in the occurrence or magnitude of estradiol-induced LH surges in KNDy ABL female mice, indicating that a complete KNDy neuronal population is not essential for normal LH surge generation. This study teases apart the contributions of different kisspeptin neural populations to the control of puberty onset, demonstrating that a majority of KNDy neurons in the arcuate nucleus are necessary for the proper timing of puberty in both sexes., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

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.

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., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

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., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Lipopolysaccharide (LPS) from Gram-negative bacteria induces an immune response and impairs reproduction through suppression of gonadotropin releasing hormone (GnRH), subsequently luteinizing hormone (LH) secretion. While there is evidence that acute inflammation inhibits kisspeptin, little is known about the impact of chronic inflammation on this key reproductive neuropeptide in livestock species. Thus, we sought to examine a central mechanism whereby LPS suppresses LH secretion in sheep. Twenty wethers were randomly assigned to one of five treatment groups: control (CON; n=4), single acute IV LPS dose (SAD; n=4), daily acute IV LPS dose (DAD; n=4), daily increasing IV LPS dose (DID; n=4), and chronic subcutaneous LPS dose (CSD; n=4). On Days 1 and 7, blood samples were collected every 12 minutes for 360 minutes using jugular venipuncture. Following blood collection on Day 7, all animals were euthanized, brain tissue was perfused with 4% paraformaldehyde, and hypothalamic blocks were removed and processed for immunohistochemistry. On Day 1, LH pulse frequency was significantly lower (p=0.02) in SAD (0.25 ± 0.1 pulses/hour), DAD (0.25 ± 0.1 pulses/hour), DID (0.35 ± 0.1 pulses/hour), and CSD (0.40 ± 0.1 pulses/hour) compared to CON (0.70 ±0.1 pulses/hour). On Day 7, only DID animals (0.35 ± 0.1 pulses/hour) had significantly lower (p=0.049) LH pulse frequency compared to controls (0.85 ± 0.1 pulse/hour). Furthermore, only DID animals (33.3 ± 10.9 cells/section/animal) had significantly fewer (p=0.001) kisspeptin-immunopositive cells compared to controls (82.6 ± 13.6 cells/section/animal). Taken together, we suggest that daily increasing doses of LPS is a powerful inhibitor of kisspeptin neurons in young male sheep and a physiologically relevant model to examine the impact of chronic inflammation on the reproductive axis in livestock., Competing Interests: Declaration of competing interest The authors report no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2024 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Introduction: Gestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity., Methods: In a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters., Results: We found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women., Discussion: This study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes., Competing Interests: Declaration of competing interest The authors declare no conflicts, including financial interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Kisspeptin-10 is a peptide hormone capable of increasing circulating follicle-stimulating hormone, luteinizing hormone and testosterone levels in humans. Clinically, these effects suggest its use as a treatment for infertility. However, its testosterone-increasing effect indicates potential misuse in sports. As such, it is included in the 2024 World Anti-Doping Agency Prohibited List. This work describes the successful validation of an initial testing procedure (screening) and a confirmation procedure for kisspeptin-10 in urine using liquid chromatography-mass spectrometry. Additionally, kisspeptin-10 was incubated in human serum to mimic endogenous metabolism to improve method sensitivity, as previous research had demonstrated a rapid elimination time of only 30 min after injection (in rats). Four metabolites, corresponding to peptide fragments y9, y8, y7 and y5, were found and added to the ITP in full scan mode. A degradation product discovered during early experimentation was found to probably be caused by oxidation of the tryptophan residue into a kynurenine residue. Further research should elucidate the kinetic parameters of the reaction to improve product stability. Using the validated confirmation procedure, a black-market vial of kisspeptin-10 was analysed. The product contained no unexpected impurities, although it appeared to have undergone more degradation than the purchased reference standard., (© 2024 John Wiley & Sons Ltd.)

The neuropeptide kisspeptin (Kiss) is crucial in regulating the hypothalamic-pituitary-gonadal axis. It is produced by two main groups of neurons in the hypothalamus: the rostral periventricular region around the third ventricle and the arcuate nucleus. Kiss is the peptide product of the KiSS-1 gene and serves as the endogenous agonist for the GPR54 receptor. The Kiss/GPR54 system functions as a critical regulator of the reproductive system. Thus, we examined the effect of intracerebroventricular administration of 3 μg of Kiss to the right lateral ventricle of ovariectomized rats primed with a dose of 5 μg subcutaneous (sc) of estradiol benzoate (EB). Kiss treatment increased the lordosis quotient at all times tested. However, the lordosis reflex score was comparatively lower yet still significant compared to the control group. To investigate receptor specificity and downstream mechanisms on lordosis, we infused 10 μg of GPR54 receptor antagonist, Kiss-234, 5 μg of the progestin receptor antagonist, RU486, or 3 μg of antide, a gonadotropin-releasing hormone-1 (GnRH-1) receptor antagonist, to the right lateral ventricle 30 min before an infusion of 3 μg of Kiss. Results demonstrated a significant reduction in the facilitation of lordosis behavior by Kiss at 60 and 120 min when Kiss-234, RU486, or antide were administered. These findings suggest that Kiss stimulates lordosis expression by activating GPR54 receptors on GnRH neurons and that Kiss/GPR54 system is an essential intermediary by which progesterone activates GnRH., (Copyright © 2024. Published by Elsevier Inc.)

Miscarriage is a common adverse pregnancy outcome with physical and emotional effects. Identifying predictive miscarriage biomarkers should improve early detection and management. Serum kisspeptin, known for its critical role in reproductive biology, has emerged as a potential biomarker for miscarriage. With this systematic review and meta-analysis, we aimed to assess the association between serum kisspeptin levels and the miscarriage risk. We systematically searched PubMed, Embase, and Cochrane Library databases for studies published up to February 2024, examining the association between serum kisspeptin levels and miscarriage. Eligible studies were observational designs that reported kisspeptin levels in women with and without miscarriage. We included 12 studies involving 2,050 participants. Pooled analysis demonstrated that low serum kisspeptin levels were significantly associated with an increased risk of miscarriage (standardized mean difference = -2.750; 95%CI: -4.357 to -1.143), with substantial heterogeneity ( I 2 = 98.7%). The pooled area under the curve from three studies indicated high diagnostic accuracy (AUC = 0.903; 95%CI: 0.860-0.946). Low serum kisspeptin levels are significantly associated with an increased miscarriage risk, suggesting that kisspeptin could serve as an effective biomarker for early detection. However, the significant heterogeneity among studies and the lack of standardized measurement protocols emphasize the necessity of further research before clinical implementation. SYSTEMATIC REVIEW REGISTRATION: (Registration ID: CRD42024520639).

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The objective of this study was to elucidate the intricate interplay among miR-105-1, kisspeptin, and their synergistic influence on basic ovarian granulosa cell functions. The effects of miR-105-1 mimics or miR-105-1 inhibitor, kisspeptin (0, 1, and 10 ng/ml), and its combinations with miR-105-1 mimics on porcine granulosa cells were assessed. The expression levels of miR-105-1, viability, proliferation (accumulation of PCNA, cyclin B1, XTT-, and BrdU-positive cells), apoptosis (accumulation of bcl-2, bax, caspase 3, p53, TUNEL-positive cells), proportion of kisspeptin-positive cells, and the release of steroid hormones and IGF-I were analyzed. Transfection of cells with miR-105-1 mimics promoted cell viability and proliferation, the occurrence of kisspeptin, and the release of progesterone and IGF-I; in contrast, miR-105-1 mimics inhibited apoptosis and estradiol output. MiR-105-1 inhibitor had the opposite effect. Kisspeptin amplified the expression of miR-105-1, cell viability, proliferation, steroid hormones, and IGF-I release and reduced apoptosis. Furthermore, the collaborative action of miR-105-1 mimics and kisspeptin revealed a synergistic relationship wherein miR-105-1 mimics predominantly supported the actions of kisspeptin, while kisspeptin exhibited a dual role in modulating the effects of miR-105-1 mimics. These findings not only affirm the pivotal role of kisspeptin in regulating basic ovarian cell functions but also represent the inaugural evidence underscoring the significance of miR-105-1 in this regulatory framework. Additionally, our results show the ability of kisspeptin to promote miR-105-1 expression and the ability of miR-105-1 to promote the occurrence and effects of kisspeptin and, therefore, indicate the existence of the self-stimulating kisspeptin-miR-105-1 axis., (© 2024. The Author(s).)

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.

Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other G q -coupled receptors, enabling distinct interactions with G q . This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G q . Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor., Competing Interests: Declaration of interests H.E.X. is a founder of Cascade Pharmaceutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Kisspeptin signaling regulates energy homeostasis. Adiposity is the principal source and receiver of peripheral Kisspeptin, and adipose Kiss1 metastasis suppressor (Kiss1) gene expression is stimulated by exercise. However, whether the adipose Kiss1 gene regulates energy homeostasis and plays a role in adaptive alterations during prolonged exercise remains unknown. Here, we investigated the role of Kiss1 role in mice and adipose tissues and the adaptive changes it induces after exercise, using adipose-specific Kiss1 knockout (Kiss1 adipoq-/- ) and adeno-associated virus-induced adipose tissue Kiss1-overexpressing (Kiss1 adipoq over ) mice. We found that adipose-derived kisspeptin signal regulates lipid and glucose homeostasis to maintain systemic energy homeostasis, but in a sex-dependent manner, with more pronounced metabolic changes in female mice. Kiss1 regulated adaptive alterations of genes and proteins in tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) pathways in female gWAT following prolonged aerobic exercise. We could further show that adipose Kiss1 deficiency leads to reduced peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) protein content of soleus muscle and maximum oxygen uptake (VO 2 max) of female mice after prolonged exercise. Therefore, adipose Kisspeptin may be a novel adipokine that increases organ sensitivity to glucose, lipids, and oxygen following exercise., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

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 obese mice, 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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Kisspeptins are neuropeptides encoded by the Kiss1 gene that was discovered as a metastasis suppressor gene in melanoma and breast cancer. Kisspeptin has pivotal functions for gonadotropin-releasing hormone secretion and plays integrated roles in the hypothalamic-pituitary-gonadal axis. However, little is known about the peripheral expression of kisspeptin in ruminants, especially in the female reproductive tract. Here, the objectives of the current study were to investigate the spatial localization of kisspeptin and mRNA expression of Kiss1 and its receptor (Kiss1r) in the fallopian tubes (FT) and uterus of goats at varied reproductive activity (cyclic versus true anoestrous goats, n=6, each). Specimens of the uterus and FT were collected and fixed using paraformaldehyde to investigate the localizations of kisspeptin in the selected tissues by immunohistochemistry. Another set of samples was snape-frozen to identify the expressions of mRNAs encoding Kiss1 and Kiss1r using real-time PCR. Results revealed immunolocalizations of kisspeptin in the uterus and the FT. The staining of kisspeptin was found mainly in the mucosal epithelium of the uterus the FT, and the endometrial glands. Very intense staining of kisspeptin was found in the uterine and FT specimens in the true anoestrous goats compared to that in cyclic ones. The expression of mRNA encoding Kiss1 gene was significantly higher in the uterine specimen of cyclic goats (1.00±0.09) compared to that in the true anoestrous goats (0.62±0.08) (P ˂0.05), while the expression of mRNA encoding Kiss1r was significantly (P ˂0.001) higher in the uterine tissues of true anoestrous goats (1.78±0.17) compared to that in cyclic ones (1.00±0.11). In conclusion, immunohistochemical localization of kisspeptin and the expression of mRNA encoding Kiss1/Kiss1r revealed spatial changes in the uterus and FT of goats according to the reproductive potential of goats (cyclic versus true anoestrous goats). However, the definitive local role of kisspeptin in the uterus and FT need further investigation., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest for this paper., (Copyright © 2024. Published by Elsevier Inc.)

Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary-gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated., Objective: To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies., Methods: In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed., Results: The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males., Conclusion: We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 μg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Kisspeptin is a multifunctional neurohormone, primarily involved in the regulation of reproduction. We tested whether peripheral administration of kisspeptin10 (KP-10) via intraperitoneal injection or slow release affects reproductive hormones and metabolites in Sterlet sturgeon (Acipenser ruthenus). Plasma and mucus 17β-estradiol (E 2 ), and testosterone (T), plasma and follicular vitellogenin (VTG) and calcium (Ca) as well as glucose and lipids were determined. Mature Sterlet sturgeon were grouped into six groups: saline i.p injection (control), human kisspeptin (hKP-10) i.p injection; acipenser kisspeptin (aKP-10) i.p injection; hKP-10 (slow release); aKP-10 (slow-release) and no treatment control. No effect for KP-10 on sturgeon body weight was found after 4 weeks of treatment. Multivariate analysis revealed a significant disparity in plasma E 2 levels. It was significantly different between groups (time, P = 0.0022). E 2 in epithelia mucosa showed significant difference between and within groups in the acute group (time, P = 0.0252; treatment, P = 0.0423; time × treatment, P = 0.0429). T levels were unaffected by treatments (P > 0.05). The presence of synthetic aKP-10 led to an elevation in oocyte and plasma VTG levels (P < 0.05). Prolonged exposure to this peptide resulted in an increase in plasma calcium levels. Simultaneously, there was an augmentation in the number of mature follicles. Regardless of the duration of exposure, aKP-10 significantly elevated plasma glucose levels in Sterlet (P < 0.0). Additionally, KP-10 led to an increase in plasma lipids and cholesterol in Sterlet. Overall, our data support an involvement for KP-10 in the regulation of gonadal steroid hormones, oocyte maturation and metabolite levels in sturgeon, suggesting a positive role for this peptide in the reproductive physiology of this species., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Kisspeptin, a protein encoded by the KISS1 gene, functions as an essential factor in suppressing tumor growth. The intricate orchestration of cellular processes such as proliferation and differentiation is governed by the Notch1/Akt/Foxo1 signaling pathway, which assumes a central role in maintaining cellular homeostasis. In the specific context of this investigation, the focal point lies in a meticulous exploration of the intricate mechanisms underlying the regulatory effect of kisspeptin on the process of endometrial decidualization. This investigation delves into the interplay between kisspeptin and the Notch1/Akt/Foxo1 signaling pathway, aiming to elucidate its significance in the pathophysiology of recurrent spontaneous abortion (RSA)., Methods: We enrolled a cohort comprising 45 individuals diagnosed with RSA, who were admitted to the outpatient clinic of the Reproductive Center at the Second Affiliated Hospital of Soochow University between June 2020 and December 2020. On the other hand, an additional group of 50 women undergoing elective abortion at the outpatient clinic of the Family Planning Department during the same timeframe was also included. To comprehensively assess the molecular landscape, Western blot and RT-qPCR were performed to analyze the expression levels of kisspeptin (and its gene KISS1 ), IGFBP1 (an established marker of decidualization), Notch1, Akt, and Foxo1 within the decidua. Human endometrial stromal cells (hESC) were given targeted interventions, including treatment with siRNA to disrupt KISS1 or exposure to kisspeptin10 (the bioactive fragment of kisspeptin), and were subsequently designated as the siKP group or the KP10 group, respectively. A control group comprised hESC was transfected with blank siRNA, and cell proliferation was meticulously evaluated with CCK8 assay. Following in vitro induction for decidualization across the three experimental groups, immunofluorescence assay was performed to identify differences in Notch1 expression and decidualization morphology between the siKP and the KP10 groups. Furthermore, RT-qPCR and Western blot were performed to gauge the expression levels of IGFBP1, Notch1, Akt, and Foxo1 across the three cell groups. Subsequently, decidualization was induced in hESC by adding inhibitors targeting Notch1, Akt, and Foxo1. The expression profiles of the aforementioned proteins and genes in the four groups were then examined, with hESC induced for decidualization without adding inhibitors serving as the normal control group. To establish murine models of normal pregnancy (NP) and RSA, CBA/J×BALB/c and CBA/J×DBA/2 mice were used. The mice were respectively labeled as the NP model and RSA model. The experimental groups received intraperitoneal injections of kisspeptin10 and kisspeptin234 (acting as a blocker) and were designated as RSA-KP10 and NP-KP234 groups. On the other hand, the control groups received intraperitoneal injections of normal saline (NS) and were referred to as RSA-NS and NP-NS groups. Each group comprised 6 mice, and uterine tissues from embryos at 9.5 days of gestation were meticulously collected for observation of embryo absorption and examination of the expression of the aforementioned proteins and genes., Results: The analysis revealed that the expression levels of kisspeptin, IGFBP1, Notch1, Akt, and Foxo1 were significantly lower in patients diagnosed with RSA compared to those in women with NP ( P <0.01 for kisspeptin and P <0.05 for IGFBP1, Notch1, Akt, and Foxo1). After the introduction of kisspeptin10 to hESC, there was an observed enhancement in decidualization capability. Subsequently, the expression levels of Notch1, Akt, and Foxo1 showed an increase, but they decreased after interference with KISS1 . Through immunofluorescence analysis, it was observed that proliferative hESC displayed a slender morphology, but they transitioned to a rounder and larger morphology post-decidualization. Concurrently, the expression of Notch1 increased, suggesting enhanced decidualization upon the administration of kisspeptin10, but the expression decreased after interference with KISS1 . Further experimentation involved treating hESC with inhibitors specific to Notch1, Akt, and Foxo1 separately, revealing a regulatory sequence of Notch1/Akt/Foxo1 ( P <0.05). In comparison to the NS group, NP mice administered with kisspeptin234 exhibited increased fetal absorption rates ( P <0.001) and decreased expression of IGFBP1, Notch1, Akt, and Foxo1 ( P <0.05). Conversely, RSA mice administered with kisspeptin10 demonstrated decreased fetal absorption rates ( P <0.001) and increased expression levels of the aforementioned molecules ( P <0.05)., Conclusion: It is suggested that kisspeptin might exert its regulatory influence on the process of decidualization through the modulation of the Notch1/Akt/Foxo1 signaling cascade. A down-regulation of the expression levels of kisspeptin could result in suboptimal decidualization, which in turn might contribute to the development or progression of RSA., Competing Interests: 利益冲突　永生化人子宫内膜基质细胞（hESC）为厦门大学医学与生命科学学院王海滨教授馈赠。除此之外，所有作者均声明不存在利益冲突。, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

This study unravels the intricate interplay between photoperiod, melatonin, and kisspeptin to orchestrate the pubertal onset of Common carp. Female fingerlings exposed to long days (LD) exhibited a hormonal crescendo, with upregulated hypothalamic-pituitary-ovarian (HPO) axis genes (kiss1, kiss1r, kiss2, gnrh2, gnrh3) and their downstream targets (lhr, fshr, ar1, esr1). However, the expression of the melatonin receptor (mtnr1a) diminished in LD, suggesting a potential inhibitory role. This hormonal symphony was further amplified by increased activity of key transcriptional regulators (gata1, gata2, cdx1, sp1, n-myc, hoxc8, plc, tac3, tacr3) and decreased expression of delayed puberty genes (mkrn1, dlk1). In contrast, short days (SD) muted this hormonal chorus, with decreased gnrh gene and regulator expression, elevated mtnr1a, and suppressed gonadal development. In in-vitro, estradiol mimicked the LD effect, boosting gnrh and regulator genes while dampening mtnr1a and melatonin-responsive genes. Conversely, melatonin acted as a conductor, downregulating gnrh and regulator genes and amplifying mtnr1a. Our findings illuminate the crucial roles of melatonin and kisspeptin as opposing forces in regulating pubertal timing. LD-induced melatonin suppression allows the kisspeptin symphony to flourish, triggering GnRH release and, ultimately, gonadal maturation. This delicate dance between photoperiod, melatonin, and kisspeptin orchestrates common carp's transition from juvenile to reproductive life., (© 2024 Wiley Periodicals LLC.)

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., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Objective: We examined how the sex steroids influence the synthesis of gonadotropins., Materials and Methods: The effects of sex steroids estradiol (E2), progesterone (P4), and dihydrotestosterone (DHT) in pituitary gonadotroph cell model (LβT2 cells) in vitro and ovary-intact rats in vivo were examined. The effects of sex steroids on Kiss1 gene expression in the hypothalamus were also examined in ovary-intact rats., Results: In LβT2 cells, E2 increased common glycoprotein alpha (Cga) and luteinizing hormone beta (Lhb) subunit promoter activity as well as their mRNA expression. Although gonadotropin subunit promoter activity was not modulated by P4, Cga and Lhb mRNA expression was increased by P4. DHT inhibited Cga and Lhb mRNA expression with a concomitant decrease in their promoter activity. During the 2-week administration of exogenous E2 to ovary-intact rats, the estrous cycle determined by vaginal smears was disrupted. P4 or DHT administration completely eliminated the estrous cycle. Protein expression of all three gonadotropin subunits within the pituitary gland was inhibited by E2 or P4 treatment in vivo; however, DHT reduced Cga expression but did not modulate Lhb or follicle-stimulating hormone beta subunit expression. E2 administration significantly repressed Kiss1 mRNA expression in a posterior hypothalamic region that included the arcuate nucleus. P4 and DHT did not modulate Kiss1 mRNA expression in this region. In contrast, P4 administration significantly inhibited Kiss1 mRNA expression in the anterior region of the hypothalamus that included the anteroventral periventricular nucleus. The expression of gonadotropin-releasing hormone (Gnrh) mRNA in the anterior hypothalamic region, where the preoptic area is located, appeared to be decreased by treatment with E2 and P4., Conclusion: Our findings suggest that sex steroids have different effects in the hypothalamus and pituitary gland., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The aim of the study was to assess concentrations of the following neuropeptides: phoenixin, spexin and kisspeptin in venous blood serum of children and adolescents suffering from bipolar disorder, and by this their predictive efficiency in this disorder., Methods: The study covered 75 individuals with a mean age of 15.26 years (95% CI: 14.86-15.67), of which the study group comprised of 57 individuals diagnosed with bipolar affective disorder and the control group - 18 individuals with no psychiatric diagnosis and no pharmacological treatment. Phoenixin, spexin and kisspeptin levels were determined in the peripheral venous blood serum. Neuropeptide concentrations were measured with the enzyme-linked immunosorbent assay (ELISA)., Results: The mean phoenixin concentration in the studied group equalled 1.57 ng/ml (95% CI: 1.35-1.79), while in the control group - 2.69 ng/ml (95% CI: 2.38-3; U Mann-Whitney test p-value < 0.05). For spexin, these results were 639.65 pg/ml (95% CI: 558.86-720.44) in the studied group, and 354.28 pg/ml (95% CI: 310.33-398.22; U Mann-Whitney test p-value < 0.05) in the control group. The observed differences were statistically significant. The mean concentration of kisspeptin levels in the studied group was 126.02 pg/ml (95% CI: 39.82-212.23; median: 59.85), while in the control group - 54.83 pg/ml (95% CI: 39.23-70.43; median: 51.3; U Mann-Whitney test p-value = 0.29), and the observed difference was not statistically significant., Conclusions: The occurrence of bipolar disorder symptoms is statistically significantly linked with a decreased phoenixin concentration and to a small degree - with an increased spexin concentration in blood serum of patients. However, it is not linked with the kisspeptin concentration.

The neuroendocrine system that controls the preovulatory surge of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH), which triggers ovulation in female mammals, is sexually differentiated in rodents. A transient increase in circulating testosterone levels in male rats within a few hours of birth is primarily responsible for the defeminization of anteroventral periventricular nucleus (AVPV) kisspeptin neurons, which are critical regulators of the GnRH/LH surge. The present study aimed to determine whether neonatal estradiol-17β (E2) converted from testosterone by aromatase primarily causes the defeminization of AVPV kisspeptin neurons and the surge of GnRH/LH in male rodents. The results of the present study showed that the neonatal administration of letrozole (LET), a nonsteroidal aromatase inhibitor, within 2 hours of birth rescued AVPV Kiss1 expression and the LH surge in adult male rats, while the neonatal administration of testosterone propionate (TP) irreversibly attenuated AVPV Kiss1 expression and the LH surge in adult female rats. Furthermore, the neonatal LET-treated Kiss1-Cre-activated tdTomato reporter males exhibited a comparable number of AVPV Kiss1-Cre-activated tdTomato-expressing cells to that of vehicle-treated female rats, while neonatal TP-treated females showed fewer AVPV Kiss1-Cre-activated tdTomato-expressing cells than vehicle-treated females. Moreover, neonatal TP administration significantly decreased the number of arcuate Kiss1-expressing and Kiss1-Cre-activated tdTomato-positive cells and suppressed LH pulses in adult gonadectomized female rats; however, neonatal LET administration failed to affect them. These results suggest that E2 converted from neonatal testosterone is primarily responsible for the defeminization of AVPV kisspeptin neurons and the subsequent GnRH/LH surge generation in male rats., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The present study was conducted to elucidate (1) the influence of kisspeptin (KP) on the in vitro development of preantral follicles (PFs) and (2) evolution of KP receptor gene ( KISS1R ) expression during ovarian follicular development in sheep. Kisspeptin was supplemented (0-100 µg/ml) in the culture medium of PFs for 6 days. The cumulus-oocyte complexes (COCs) from cultured PFs were subsequently matured to metaphase II (MII) for an additional 24 h. The proportions of PFs exhibiting growth, antrum formation, average increase in diameter, and maturation of oocytes to MII stage were the indicators of follicular development in vitro . The expression of the kisspeptin receptor gene at each development stages of in vivo developed (preantral, early antral, antral, large antral and COCs from Graafian follicles) and in vitro cultured PFs supplemented with KP was assessed using a real-time polymerase chain reaction. The best development in all the parameters under study was elicited with 10 µg/ml of KP. Supplementation of KP (10 µg/ml) in a medium containing other growth factors (insulin-like growth factor-I) and hormones (growth hormone, thyroxine, follicle-stimulating hormone) resulted in better PF development. The KISS1R gene was expressed in follicular cells and oocytes at all the development stages of both in vivo developed and in vitro cultured follicles. Higher KISS1R gene expression was supported by culture medium containing KP along with other hormones and growth factors. Accordingly, it is suggested that one of the mechanisms through which KP and other growth factors and hormones influence the ovarian follicular development in mammals is through the upregulation of expression of the KP receptor gene.

At this time, with advances in medical science, many cancers and chronic diseases are treatable, but one of their side effects is infertility. Some women also want to delay pregnancy for personal reasons. There has been some evidence that kisspeptin activates broad signals by binding to its receptor, suggesting that the role of kisspeptin in direct control of ovarian function includes follicle growth and steroid production. In this study, the effect of kisspeptin on improving the quality and results for human ovarian follicles was investigated. A section of ovary was removed laparoscopically from women between 20 and 35 years of age ( n = 12). Pieces were divided randomly into two groups, control and treatment (with 1 μM kisspeptin). Real-time PCR was performed for GDF9 , BMP15 and mTOR gene expression assessments. Western blotting was carried out to measure AKT and FOXO3a protein expression. Data were analyzed using one-way analysis of variance (ANOVA) and Tukey's test; means were considered significantly different at a P -value < 0.05. During treatment with the kisspeptin group, maturity genes are expressed. Therefore, kisspeptin is an effective substance to improve the quality of the human ovarian medium as it increases the maturity of follicles.

Grass puffer is a semilunar-synchronized spawner: spawning occurs on beaches only for several days of spring tide around new moon (lunar age 0) and full moon (lunar age 15) every 2 weeks from spring to early summer. To investigate the role of kisspeptin and gonadotropin-inhibitory hormone (GnIH) in the semilunar-synchronized spawning, lunar age-dependent expression of the genes encoding kisspeptin ( kiss2 ), kisspeptin receptor ( kissr2 ), GnIH ( gnih ), GnIH receptor ( gnihr ), gonadotropin-releasing hormone 1 (GnRH1) ( gnrh1 ), and three gonadotropin (GTH) subunits ( gpa , fshb , lhb ) was examined in the male grass puffer, which was kept in an aquarium under natural light condition in a lunar month during the spawning period. In the brain, both kiss2 and kissr2 showed lunar variations with a peak at lunar age 10, while both gnih and gnihr showed semilunar variations with two peaks at lunar age 0 and 20. On the other hand, gnrh1 showed semilunar variation with two peaks at lunar age 0 and 15. In the pituitary, kiss2 , kissr2 , gnih , and gnihr showed similar variations to those shown in the brain. The fshb and lhb mRNA levels showed semilunar variations with two peaks at lunar age 0 and 15. The present study shows lunar and semilunar oscillations of kiss2 / kissr2 and gnih / gnihr expressions, respectively, with their peaks around spring tide in the brain and pituitary along with the semilunar expressions of gnrh1 and the pituitary GTH subunit genes. These results suggest that the lunar age-dependent expressions of the kisspeptin, GnIH, and their receptor genes may be primarily important in the control of the precisely timed semilunar spawning of the grass puffer.

Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) ( n  = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.

Background: Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth., Methods: Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models., Results: Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness., Conclusion: The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Yang, Chen, Yuan, Chen, Liang, Miao, He and Wang.)

Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism and a failure of pubertal development. Over the past 2 decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP's function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders. The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel nonsteroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome, uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Endometrial polyp (EP) is a type of pathology that is quite common in clinical practice. Although its exact etiology is not fully known, there is evidence to support that it is sensitive to hormonal stimuli. We aimed to investigate the relationship between kisspeptin (KP) and EP by comparing the genetic (tissue-blood) and immunohistochemical (IHC) expression of KP in EP lesions in patients with normal endometrial findings., Materials and Methods: A prospective case-control study of 50 patients with EP (N = 25) and normal endometrial findings (N = 25) on biopsy and/or excision material was performed. Blood and biopsy samples obtained from all patients were stored at -80 °C. KP gene expression levels were determined from paraffin blocks, and peripheral venous blood samples obtained from biopsy specimens and IHC-H-score analysis were performed from paraffin blocks. EP and matched controls were compared for KP., Results: After IHC, the KP H-score of the control group was higher than the EP group, and this difference was statistically significant; H-score: control: 5 (++; 1-15); polyp: 1 (+; 0-12) (P &lt; 0.05). Although KP expression in both tissue and blood was higher in the control group than in the EP group, this difference was not statistically significant (P &gt; 0.05). No significant correlation was found between IHC H-score and KP expression levels in tissue and blood. According to the ROC analysis, the tissue and blood KP expression cut-off value and area under the curve (AUC) predicting the likelihood of developing EP were not significant (tissue KP: 1.04, AUC: 0.570, P = 0.388, sensitivity 56%, specificity 60%, Blood KP: 1.06, AUC: 0.569, P = 0.401, sensitivity 80%, specificity 40%)., Conclusions: Decreased KP expression level in EP lesions may predict the diagnosis of EP, and in the future, KP may have therapeutic potential for benign gynecological pathologies such as polyps.

Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory dysfunctions, male infertility, polycystic ovary syndrome, and tubule disease. The remaining 15% have infertility for unknown reasons, including lifestyle and environmental factors. The regulation of the hypothalamic- pituitary-adrenal axis (HPA) is crucial for the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are essential for female reproductive functions. GnRH is the primary reproductive axis regulator. The pattern of GnRH, FSH, and LH release is determined by its pulsatile secretion, which in turn controls endocrine function and gamete maturation in the gonads. Peptides called Kisspeptin (KP), Neurokinin-B (NKB), and Orexin influence both positive and negative feedback modulation of GnRH, FSH, and LH secretion in reproduction. This review article mainly focuses on the historical perspective, isoform, and signaling pathways of KP, NKB, and Orexin novel peptide-based targets including clinical and preclinical studies and having a promising effect in the management of infertility., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice., Methods: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period., Results: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice., Conclusion: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported., Objective: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial)., Design: Two randomized, placebo-controlled, parallel-group, dose-finding trials., Setting: Clinical trials unit., Patients: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75)., Interventions: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5)., Main Outcome Measures: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound., Results: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 μg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 μg), 88% (1 μg), 82% (0.3 μg), and 75% (0.1 μg), of women after MVT-602, 100% after triptorelin and 60% after placebo., Conclusions: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR., Clinical Trial Registration Number: EUDRA-CT: 2017-003812-38, 2018-001379-20., Competing Interests: Declaration of interests A.A. reports Myovant Sciences Ltd Consultancy Fee and NIHR Clinician Scientist Fellowship for the submitted work. M.U. has nothing to disclose. C.V.-P. is an employee of QPS Netherlands BV. L.B. reports contracting consultant to Myovant Sciences outside the submitted work. M.E. has nothing to disclose. R.W. has nothing to disclose. T.-Y.L. has nothing to disclose. J.C.A.F. has nothing to disclose. E.M has nothing to disclose. W.S.D. reports consulted for Myovant Sciences Ltd. for the submitted work; NIHR research professorship; consulting fees from Myovant Sciences outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing was used to achieve a 60-70% knockdown in estrogen receptor alpha (ESR1) expression by GABA neurons located within the regions of the rostral periventricular area of the third ventricle (RP3V) and medial preoptic nuclei (MPN) in adult female mice. Mice exhibited variable reproductive phenotypes with the only significant finding being mice with bilateral ESR1 deletion in RP3V GABA neurons having reduced cFos expression in gonadotropin-releasing hormone (GnRH) neurons at the time of the surge. One sub-population of RP3V GABA neurons expresses kisspeptin. Re-grouping ESR1-edited mice on the basis of their RP3V kisspeptin expression revealed a highly consistent phenotype; mice with a near-complete loss of kisspeptin immunoreactivity displayed constant estrus and failed to exhibit surge activation but retained pulsatile luteinizing hormone (LH) secretion. These observations demonstrate that ESR1-expressing GABA-kisspeptin neurons in the RP3V are essential for the murine preovulatory LH surge mechanism., Competing Interests: JC, SY, RP, AK, AH, AH No competing interests declared, (© 2023, Clarkson et al.)

Introduction The purpose of this study was to determine the association between kisspeptin levels and obesity in patients with polycystic ovary syndrome (PCOS) or in healthy controls and to explore the correlation between levels of kisspeptin and various endocrine and metabolic indices in each group. Methods From August 2020 to December 2021, the clinical data of 78 patients with polycystic ovary syndrome and 78 healthy individuals were collected. The two groups were further divided into obese and non-obese groups based on a BMI cutoff of 25. Serum kisspeptin levels were measured using enzyme linked immunosorbent assay (ELISA). Pearson's correlation analysis was used to determine the correlation between PCOS and kisspeptin levels. Results The weight, body mass index (BMI), and waist circumference (WC), estradiol (E2), and testosterone (T) of the obese PCOS group were significantly higher than those of the study group ( p  < .05). WC, kisspeptin, triglycerides (TG), glucose (GLU), alanine amiotransferase (ALT), blood urea nitrogen (BUN), uric acid (UA), E2, luteinizing hormone (LH), prolactin (PRL), and T in the non-obese PCOS group were higher than those in the control group, and the difference was statistically significant ( p  < .05). Levels of E2 and TG in the obese PCOS group were significantly higher than those in the non-obese PCOS group ( p  < .05). Kisspeptin levels in the PCOS group exhibited a significant positive correlation with LH, T, and AMH levels; kisspeptin level positively correlated with T in the non-obese PCOS group and with anti-Müllerian hormone (AMH) in the obese PCOS group. Conclusion Serum kisspeptin levels are associated with hormone levels in patients with PCOS. Kisspeptin correlates with distinct biochemical indices in obese versus non-obese groups, indicating that kisspeptin may play a role in the prognostication, treatment, and clinical evaluation of patients with varying BMI.

Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal axis. KP acts together with dynorphin A (encoded by Pdyn) and neurokinin B (encoded by Tac2) to regulate reproduction. KP is crucial for the onset of puberty and is under the control of sirtuin (encoded by Sirt1). We hypothesize that the maternal cafeteria (CAF) diet has adverse effects on the offspring's hormonal, metabolic, and reproductive functions due to sex-specific alterations in the expression of Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 in the hypothalamus, and Kiss1, Gpr54, and Sirt1 in the liver. Rats were fed a CAF diet before pregnancy, during pregnancy, and during lactation. The vaginal opening was monitored. Offspring were sacrificed in three age points: PND 30, PND 35, and PND 60 (females) and PND 40, PND 45, and PND 60 (males). Their metabolic and hormonal status was assessed. mRNA for Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 were measured by real-time PCR in the hypothalamus and/or livers. We found that CAF offspring had lower weight and altered body composition; increased cholesterol and triglyceride levels, sex-specific changes in glucose and insulin levels; sex-dependent changes in Sirt1/Kiss1 mRNA ratio in the hypothalamus; sex-specific alterations in Kiss1 and Sirt1 mRNA in the liver with more diversity in males; and a delayed puberty onset in females. We concluded that the mother's CAF diet leads to sex-specific alterations in metabolic and reproductive outcomes via Kiss1/Gpr54 and Sirt1 systems in offspring., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive pulsatile hormone secretion remains unclear in females. In order to study spontaneous synchronization within the ARNKISS neuron network, acute brain slices were prepared from adult female Kiss1-GCaMP6 mice. Analysis of both spontaneous synchronizations and those driven by high frequency stimulation of individual ARNKISS neurons revealed that the network exhibits semi-random emergent excitation dependent upon glutamate signaling through AMPA receptors. No role for NMDA receptors was identified. In contrast to male mice, ongoing tachykinin receptor tone within the slice operated to promote spontaneous synchronizations in females. As previously observed in males, we found that ongoing dynorphin transmission in the slice did not contribute to synchronization events. These observations indicate that a very similar AMPA receptor-dependent mechanism underlies ARNKISS neuron synchronizations in the female mouse supporting the "glutamate two-transition" model for kisspeptin neuron synchronization. However, a potentially important sex difference appears to exist with a more prominent facilitatory role for tachykinin transmission in the female., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Hypothalamic kisspeptin neurons are master regulators of mammalian reproduction via direct stimulation of gonadotropin-releasing hormone and consequent gonadotropin release. Here, we generated novel Kiss1 (kisspeptin gene)-Cre rats and investigated the developmental changes and sex differences in visualized Kiss1 neurons of Kiss1-Cre-activated tdTomato reporter rats. First, we validated Kiss1-Cre rats by generating Kiss1-expressing cell-specific Kiss1 knockout (Kiss1-KpKO) rats, which were obtained by crossing the current Kiss1-Cre rats with Kiss1-floxed rats. The resulting male Kiss1-KpKO rats lacked Kiss1 expression in the brain and exhibited hypogonadotropic hypogonadism, similar to the hypogonadal phenotype of global Kiss1 KO rats. Histological analysis of Kiss1 neurons in Kiss1-Cre-activated tdTomato reporter rats revealed that tdTomato signals in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) were not affected by estrogen, and that tdTomato signals in the ARC, AVPV, and medial amygdala (MeA) were sexually dimorphic. Notably, neonatal AVPV tdTomato signals were detected only in males, but a larger number of tdTomato-expressing cells were detected in the AVPV and ARC, and a smaller number of cells in the MeA was detected in females than in males at postpuberty. These findings suggest that Kiss1-visualized rats can be used to examine the effect of estrogen feedback mechanisms on Kiss1 expression in the AVPV and ARC. Moreover, the Kiss1-Cre and Kiss1-visualized rats could be valuable tools for further detailed analyses of sexual differentiation in the brain and the physiological role of kisspeptin neurons across the brain in rats.

Kisspeptin (KP) is a group of hypothalamic neuropeptides encoded by KISS-1 gene. KP-54, a 54-amino-acid peptide, helps regulate the hypothalamic-pituitary-ovarian axis and plays a potential role in implantation. C57BL/6 J female mice were superovulated via intraperitoneal injection of 5 International Units (IU) pregnant mare serum gonadotrophin (day 1). Forty-eight hours later, mice (5/group) were injected with phosphate-buffered saline (PBS) (group A), 5 IU human chorionic gonadotrophin (hCG) (group B), or 3 nmol KP-54 (group C). On day 7, mice were euthanized and uteri excised to create paraformaldehyde-fixed paraffin-embedded sections that were immunostained for the implantation markers: leukemia inhibitory factor (LIF) and integrin αVβ3 (ITG αVβ3). Slides were scored for intensity of staining in endometrial glandular epithelium (GE) and stromal cells (SCs) via histoscore (H-score). Data were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons. LIF expression was significantly higher in GE and SCs of mice triggered with KP-54 compared to placebo (P = .009 for both), but only higher than hCG trigger group in SCs (P = .009). Meanwhile, ITG αVβ3 expression was significantly higher in SCs of mice triggered with KP-54 compared to placebo (P = .028). In conclusion, using KP-54 as an ovulation trigger resulted in higher expression of the implantation markers LIF and ITG αVβ3 in mice endometrium compared to hCG or placebo. This suggests a potential role for KP-54 trigger in improving embryo implantation in clinical IVF. However, further studies are needed to correlate these results with clinical implantation rates and pregnancy outcomes., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

The current model for the synchronization of GnRH neural activity driving GnRH and LH pulses proposes that a set of arcuate (ARC) neurons that contain kisspeptin, neurokinin B, and dynorphin (KNDy neurons) is the GnRH pulse generator. This study tested the functional role of ovine KNDy neurons in pulse generation and explored the roles of nearby Kiss1 receptor (Kiss1R)-containing cells using lesions produced with saporin (SAP) conjugates. Injection of NK3-SAP ablated over 90% of the KNDy cells, while Kiss-SAP (saporin conjugated to kisspeptin-54) lesioned about two-thirds of the Kiss1R population without affecting KNDy or GnRH cell number. Both lesions produced a dramatic decrease in LH pulse amplitude but had different effects on LH pulse patterns. NK3-SAP increased interpulse interval, but Kiss-SAP did not. In contrast, Kiss-SAP disrupted the regular hourly occurrence of LH pulses, but NK3-SAP did not. Because Kiss1R is not expressed in KNDy cells, HiPlex RNAScope was used to assess the colocalization of 8 neurotransmitters and 3 receptors in ARC Kiss1R-containing cells. Kiss1R cells primarily contained transcript markers for GABA (68%), glutamate (28%), ESR1 (estrogen receptor-α) mRNA, and OPRK1 (kappa opioid receptor) mRNA. These data support the conclusion that KNDy neurons are essential for GnRH pulses in ewes, whereas ARC Kiss1R cells are not but do maintain the amplitude and regularity of GnRH pulses. We thus propose that in sheep, ARC Kiss1R neurons form part of a positive feedback circuit that reinforces the activity of the KNDy neural network, with GABA or glutamate likely being involved., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We aimed to investigate whether maternal serum kisspeptin levels are associated with late-onset FGR and contribute to adverse perinatal outcomes., Method: In this case-control study, a total of 90 pregnant women admitted to the perinatology clinic were enrolled. Forty-five of them were diagnosed with FGR and 45 women with healthy pregnancies formed the control group. Maternal serum levels of kisspeptin 1 were compared., Results: Median kisspeptin1 serum levels were higher in the group of patients with FGR according to gestational age than in the control group [79.4(3.9-230.2) pg/mL vs. 39.8(0.4-188.3) pg/mL; p = 0.001]. The optimal cut-off value for kisspeptin1 was 30.32 pg/mL, with a positive predictive value of 64.6% (95% CI; 0.54-0.86), negative predictive value of 87.5% (95% CI; 0.44-0.72), positive likelihood ratio 1.75 (95% CI; 1.31-2.32), negative likelihood ratio 0.14 (95% CI; 0.04-0.44)., Discussion: Kisspeptin1 differed significantly in late-onset FGR compared with the control group. This difference from the control group can be used to estimate late-onset FGR., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)