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Peptides Apr 2023Optical systems and genetic engineering technologies have made it possible to control neurons and unravel neuronal circuit behavior with high temporal and spatial...
Optical systems and genetic engineering technologies have made it possible to control neurons and unravel neuronal circuit behavior with high temporal and spatial resolution. The application of optogenetic strategies to understand the physiology of kisspeptin neuronal circuits has evolved in recent years among the neuroendocrine community. Kisspeptin neurons are fundamentally involved in controlling mammalian reproduction but also are implicated in numerous other physiological processes, including but not limited to feeding, energy expenditure, core body temperature and behavior. We conducted a review aiming to shed light on the novel findings obtained from in vitro and in vivo optogenetic studies interrogating kisspeptin neuronal circuits to date. Understanding the function of kisspeptin networks in the brain can greatly inform a wide range of clinical studies investigating infertility treatments, gender identity, metabolic disorders, hot flushes and psychosexual disorders.
Topics: Humans; Animals; Female; Male; Kisspeptins; Optogenetics; Gender Identity; Neurons; Brain; Mammals
PubMed: 36731655
DOI: 10.1016/j.peptides.2023.170961 -
Taiwanese Journal of Obstetrics &... Jun 2017
Topics: Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Receptors, Kisspeptin-1
PubMed: 28600069
DOI: 10.1016/j.tjog.2017.04.034 -
Singapore Medical Journal Dec 2015Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors... (Review)
Review
Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus. Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders. Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications. Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals. Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Estrogens; Feedback, Physiological; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Kisspeptins; Male; Mice; Neoplasms; Neurons; Protein Binding; Rats; Reproduction; Sex Factors; Signal Transduction
PubMed: 26702158
DOI: 10.11622/smedj.2015183 -
Cellular Physiology and Biochemistry :... 2018Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin... (Review)
Review
Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited. We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes. Literature searches were conducted in PubMed using keywords related to: (i) kisspeptin or receptors, kisspeptin-1 (ii) reproduction or infertility or fertility (iii) gene and (iv) dosage or measurement or quantification or serum level, in human. Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes. Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty. Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.
Topics: Fertilization in Vitro; Genetic Variation; Genitalia; Gonadotropins; Humans; Infertility; Kisspeptins; Neurons; Receptors, Kisspeptin-1; Sexual Maturation
PubMed: 30205368
DOI: 10.1159/000493406 -
Comprehensive Physiology Jul 2015The discoveries of rapid, membrane-initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of... (Review)
Review
The discoveries of rapid, membrane-initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of reproduction. Classical nuclear actions of estradiol and progesterone steroids affecting transcription are essential. However, with the discoveries of membrane-associated steroid receptors, it is becoming clear that estradiol and progesterone have neurotransmitter-like actions activating intracellular events. Ultimately, membrane-initiated actions can influence transcription. Estradiol membrane-initiated signaling (EMS) modulates female sexual receptivity and estrogen feedback regulating the luteinizing hormone (LH) surge. In the arcuate nucleus, EMS activates a lordosis-regulating circuit that extends to the medial preoptic nucleus and subsequently to the ventromedial nucleus (VMH)--the output from the limbic and hypothalamic regions. Here, we discuss how EMS leads to an active inhibition of lordosis behavior. To stimulate ovulation, EMS facilitates astrocyte synthesis of progesterone (neuroP) in the hypothalamus. Regulation of GnRH release driving the LH surge is dependent on estradiol-sensitive kisspeptin (Kiss1) expression in the rostral periventricular nucleus of the third ventricle (RP3V). NeuroP activation of the LH surge depends on Kiss1, but the specifics of signaling have not been well elucidated. RP3V Kiss1 neurons appear to integrate estradiol and progesterone information which feeds back onto GnRH neurons to stimulate the LH surge. In a second population of Kiss1 neurons, estradiol suppresses the surge but maintains tonic LH release, another critical component of the estrous cycle. Together, evidence suggests that regulation of reproduction involves membrane action of steroids, some of which are synthesized in the brain.
Topics: Animals; Brain; Female; Gonadal Steroid Hormones; Gonadotropins, Pituitary; Humans; Kisspeptins; Receptors, Estradiol; Reproduction; Signal Transduction
PubMed: 26140715
DOI: 10.1002/cphy.c140056 -
Frontiers in Endocrinology 2022Kisspeptins (KPs) secreted from the hypothalamic KP neurons act on KP receptors (KPRs) in gonadotropin (GPN) releasing hormone (GnRH) neurons to produce GnRH. GnRH acts... (Review)
Review
Kisspeptins (KPs) secreted from the hypothalamic KP neurons act on KP receptors (KPRs) in gonadotropin (GPN) releasing hormone (GnRH) neurons to produce GnRH. GnRH acts on pituitary gonadotrophs to induce secretion of GPNs, namely follicle stimulating hormone (FSH) and luteinizing hormone (LH), which are essential for ovarian follicle development, oocyte maturation and ovulation. Thus, hypothalamic KPs regulate oocyte maturation indirectly through GPNs. KPs and KPRs are also expressed in the ovarian follicles across species. Recent studies demonstrated that intraovarian KPs also act directly on the KPRs expressed in oocytes to promote oocyte maturation and ovulation. In this review article, we have summarized published reports on the role of hypothalamic and ovarian KP-signaling in oocyte maturation. Gonadal steroid hormones regulate KP secretion from hypothalamic KP neurons, which in turn induces GPN secretion from the hypothalamic-pituitary (HP) axis. On the other hand, GPNs secreted from the HP axis act on the granulosa cells (GCs) and upregulate the expression of ovarian KPs. While KPs are expressed predominantly in the GCs, the KPRs are in the oocytes. Expression of KPs in the ovaries increases with the progression of the estrous cycle and peaks during the preovulatory GPN surge. Intrafollicular KP levels in the ovaries rise with the advancement of developmental stages. Moreover, loss of KPRs in oocytes in mice leads to failure of oocyte maturation and ovulation similar to that of premature ovarian insufficiency (POI). These findings suggest that GC-derived KPs may act on the KPRs in oocytes during their preovulatory maturation. In addition to the intraovarian role of KP-signaling in oocyte maturation, , a direct role of KP has been identified during maturation of sheep, porcine, and rat oocytes. KP-stimulation of rat oocytes, , resulted in Ca release and activation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1 and 2. treatment of rat or porcine oocytes with KPs upregulated messenger RNA levels of the factors that favor oocyte maturation. In clinical trials, human KP-54 has also been administered successfully to patients undergoing assisted reproductive technologies (ARTs) for increasing oocyte maturation. Exogenous KPs can induce GPN secretion from hypothalamus; however, the possibility of direct KP action on the oocytes cannot be excluded. Understanding the direct and roles of KP-signaling in oocyte maturation will help in developing novel KP-based ARTs.
Topics: Animals; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Luteinizing Hormone; Mice; Oocytes; Oogenesis; Rats; Sheep; Swine
PubMed: 36072937
DOI: 10.3389/fendo.2022.917464 -
Journal of Neuroendocrinology May 2022GnRH is the pivotal hormone in controlling the hypothalamic-pituitary gonadal (HPG) axis in humans and other mammalian species. GnRH function is influenced by a... (Review)
Review
GnRH is the pivotal hormone in controlling the hypothalamic-pituitary gonadal (HPG) axis in humans and other mammalian species. GnRH function is influenced by a multitude of known and still unknown environmental and genetic factors. Molecular genetic studies on human families with hypogonadotropic hypogonadism over the past two decades have been instrumental in delineating the kisspeptin and neurokinin B signalling, which integrally modulates GnRH release from the hypothalamus. The identification of kisspeptin and neurokinin B ligand-receptor gene pair mutations in patients with absent puberty have paved the way to a greater understanding of the central regulation of the HPG cascade. In this article, we aim to review the literature on the genetic and clinical aspects of GnRH and its receptor, as well as the two ligand-receptor sets directly pertinent to the function of GnRH hormone signalling, kisspeptin/ kisspeptin receptor and NKB/NK3R.
Topics: Animals; Gonadotropin-Releasing Hormone; Human Genetics; Humans; Kisspeptins; Ligands; Mammals; Neurokinin B
PubMed: 34970798
DOI: 10.1111/jne.13080 -
Current Opinion in Pharmacology Dec 2022Gonadotropin-releasing hormone (GnRH) is the final output of the central nervous system that drives fertility. A characteristic of GnRH secretion is its pulsatility,... (Review)
Review
Gonadotropin-releasing hormone (GnRH) is the final output of the central nervous system that drives fertility. A characteristic of GnRH secretion is its pulsatility, which is driven by a pulse generator. Each GnRH pulse triggers a luteinizing hormone (LH) pulse. However, the puzzle has been to reconcile the synchronicity of GnRH neurons with the scattered hypothalamic distribution of their cell bodies. A leap toward understanding GnRH pulses was the discovery of kisspeptin neurons near the distal processes of GnRH neurons, which secrete kisspeptins, potent excitatory neuropeptides on GnRH neurons, and equipped with dual, but opposite, self-modulatory neuropeptides, neurokinin B and dynorphin. Over the last decade, this cell-to-cell communication has been dissected in animal models. Today the 50-year quest for the basic mechanism of GnRH pulse generation may be over, but questions about its physiological tuning remain. Here is an overview of recent basic research that frames translational research.
Topics: Animals; Gonadotropin-Releasing Hormone; Arcuate Nucleus of Hypothalamus; Neurokinin B; Kisspeptins; Neurons
PubMed: 36347163
DOI: 10.1016/j.coph.2022.102316 -
Nature Communications May 2023Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin...
Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.
Topics: Animals; Female; Mice; Arcuate Nucleus of Hypothalamus; Estradiol; Estrogen Receptor alpha; Estrogens; Hypothalamus; Kisspeptins; DAX-1 Orphan Nuclear Receptor
PubMed: 37248237
DOI: 10.1038/s41467-023-38618-y -
Seminars in Reproductive Medicine May 2019Hypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between... (Review)
Review
Hypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Female; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Kisspeptins; Neurons; Reproduction
PubMed: 31869841
DOI: 10.1055/s-0039-3400251