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Robert P Millar - One of the best experts on this subject based on the ideXlab platform.
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Stimulation of growth hormone by Kisspeptin antagonists in ewes
Journal of Endocrinology, 2018Co-Authors: Jeremy Troy Smith, Antonia K Roseweir, Iain J Clarke, Michael Millar, Robert P MillarAbstract:Kisspeptin signalling is indispensable for fertility, stimulating gonadotropin- releasing hormone (GnRH) secretion and mediating gonadal steroid feedback on GnRH neurons. Moreover, Kisspeptin neurons have been implicated in other non-reproductive neuroendocrine roles. Kisspeptin appears to also regulate growth hormone secretion but much of the data appear contradictory. We sought to clarify a potential role of Kisspeptin in GH regulation by examining the effect of Kisspeptin antagonists on growth hormone (GH) secretion in ewes under various physiological conditions. Our data show clear and robust increases in GH secretion following lateral ventricle or third ventricle infusion of Kisspeptin antagonists p-234 and p-271 in either ovariectomised or anestrous ewes. Central infusion of Kisspeptin-10 had no effect on GH secretion. To determine the level at which Kisspeptin may influence GH secretion we examined expression of the cognate Kisspeptin receptor, GPR54, in pituitary cells and showed by immunocytochemistry that the majority of somatotropes express GPR54 while expression was largely negative in other pituitary cells. Overall, we have demonstrated that blocking Kisspeptin signalling by antagonists stimulates GH secretion in ewes and that this is likely mediated by inhibiting endogenous Kisspeptin activation of GPR54 expressed on somatotropes. The findings suggest that endogenous Kisspeptin inhibits growth hormone secretion through GPR54 expressed on somatotropes.
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Kisspeptin Antagonists Reveal Kisspeptin 1 and Kisspeptin 2 Differential Regulation of Reproduction in the Teleost, Morone saxatilis
Biology of Reproduction, 2015Co-Authors: Nilli Zmora, Robert P Millar, John David Stubblefield, Ten-tsao Wong, Berta Levavi-sivan, Yonathan ZoharAbstract:The importance of Kisspeptin in regulating vertebrate reproduction has been well established, but the exact mechanism continues to unfold. Unlike mammals, many lower vertebrates possess a dual Kisspeptin system, Kiss1 and Kiss2. To decipher the roles of the Kisspeptins in fish, we identified two potential Kisspeptin antagonists, pep 234 and pep 359, by screening analogs for their ability to inactivate striped bass Kiss1 and Kiss2 receptors expressed in COS7 cells. Pep 234 (a mammalian KISS1 antagonist) antagonizes Kiss1r signaling activated by Kiss1 and Kiss2, and pep 359 (a novel analog) antagonizes Kiss2 activation of both receptors. In vitro studies using brain slices demonstrated that only Kiss2 can upregulate the expression of the hypophysiotropic gnrh1, which was subsequently diminished by pep 234 and pep 359. In primary pituitary cell cultures, the two antagonists revealed a complex network of putative endogenous and exogenous regulation by Kisspeptin. While both Kisspeptins stimulate Fsh expression and secretion, Kiss2 predominately induces Lh secretion. Pep 234 and 359 treatment of spawning males hindered sperm production. This effect was accompanied with decreased brain gnrh1 and gnrh2 mRNA levels and peptide content in the pituitary, and increased levels of pituitary Lh, probably due to attenuation of Lh release. Strikingly, the mRNA levels of arginine-vasotocin, the neurons of which in the preoptic area coexpress kiss2r, were dramatically reduced by the antagonists. Our results demonstrate differential actions of Kiss1 and Kiss2 systems along the hypothalamic-pituitary axis and interactions with other neuropeptides, and further reinforce the importance of Kisspeptin in the execution of spawning.
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Kisspeptin restores pulsatile lh secretion in patients with neurokinin b signaling deficiencies physiological pathophysiological and therapeutic implications
Neuroendocrinology, 2013Co-Authors: Jacques Young, Jyothis T George, Richard A Anderson, Javier A Tello, Bruno Francou, Jerome Bouligand, Anne Guiochonmantel, Sylvie Braillytabard, Robert P MillarAbstract:Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous Kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that Kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to Kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of Kisspeptin secretion. The ability of continuous Kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous Kisspeptin.
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Kisspeptin 10 is a potent stimulator of lh and increases pulse frequency in men
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Jyothis T George, Antonia K Roseweir, Robert P Millar, Johannes D Veldhuis, Claire L Newton, Elena Faccenda, Richard A AndersonAbstract:Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal Kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man. Objective: We investigated our hypothesis that Kisspeptin-10 increases GnRH and thus LH pulse frequency. Design and Participants: The dose response of Kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of Kisspeptin-10 for up to 22.5 h. Results: Intravenous bolus Kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of Kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and ser...
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Kisspeptin signalling in the hypothalamic arcuate nucleus regulates gnrh pulse generator frequency in the rat
PLOS ONE, 2009Co-Authors: Xiao Feng Li, Antonia K Roseweir, Robert P Millar, J S Kinseyjones, Yewsong Cheng, Alice M I Knox, Nikoletta A Petrou, Stafford L Lightman, Stuart MilliganAbstract:Background: Kisspeptin and its G protein-coupled receptor (GPR) 54 are essential for activation of the hypothalamopituitary-gonadal axis. In the rat, the Kisspeptin neurons critical for gonadotropin secretion are located in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. As the ARC is known to be the site of the gonadotropinreleasing hormone (GnRH) pulse generator we explored whether Kisspeptin-GPR54 signalling in the ARC regulates GnRH pulses. Methodology/Principal Findings: We examined the effects of Kisspeptin-10 or a selective Kisspeptin antagonist administration intra-ARC or intra-medial preoptic area (mPOA), (which includes the AVPV), on pulsatile luteinizing hormone (LH) secretion in the rat. Ovariectomized rats with subcutaneous 17b-estradiol capsules were chronically implanted with bilateral intra-ARC or intra-mPOA cannulae, or intra-cerebroventricular (icv) cannulae and intravenous catheters. Blood samples were collected every 5 min for 5–8 h for LH measurement. After 2 h of control blood sampling, Kisspeptin-10 or Kisspeptin antagonist was administered via pre-implanted cannulae. Intranuclear administration of Kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH lasting approximately 1 h, before recovering to a normal pulsatile pattern of circulating LH. Both icv and intra-ARC administration of Kisspeptin antagonist suppressed LH pulse frequency profoundly. However, intra-mPOA administration of Kisspeptin antagonist did not affect pulsatile LH secretion. Conclusions/Significance: These data are the first to identify the arcuate nucleus as a key site for Kisspeptin modulation of LH pulse frequency, supporting the notion that Kisspeptin-GPR54 signalling in this region of the mediobasal hypothalamus is a critical neural component of the hypothalamic GnRH pulse generator.
Robert A Steiner - One of the best experts on this subject based on the ideXlab platform.
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emerging ideas about Kisspeptin gpr54 signaling in the neuroendocrine regulation of reproduction
Trends in Neurosciences, 2007Co-Authors: Alexander S. Kauffman, Donald K Clifton, Robert A SteinerAbstract:Neurons that produce gonadotropin-releasing hormone (GnRH) drive the reproductive axis, but the molecular and cellular mechanisms by which hormonal and environmental signals regulate GnRH secretion remain poorly understood. Kisspeptins are products of the Kiss1 gene, and the interaction of Kisspeptin and its receptor GPR54 plays a crucial role in governing the onset of puberty and adult reproductive function. This review discusses the latest ideas about Kisspeptin–GPR54 signaling in the neuroendocrine regulation of reproduction, with special emphasis on the role of Kiss1 and Kisspeptin in the negative and positive feedback control of gonadotropin secretion by sex steroids, timing of puberty onset, sexual differentiation of the brain and photoperiodic regulation of seasonal reproduction.
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the Kisspeptin receptor gpr54 is required for sexual differentiation of the brain and behavior
The Journal of Neuroscience, 2007Co-Authors: Alexander S. Kauffman, Michelle L Gottsch, Donald K Clifton, Jin Ho Park, Anika A Mcphielalmansingh, Cristian Bodo, John G Hohmann, Maria N Pavlova, Alex Rohde, Robert A SteinerAbstract:GPR54 is a G-protein-coupled receptor, which binds Kisspeptins and is widely expressed throughout the brain. Kisspeptin–GPR54 signaling has been implicated in the regulation of pubertal and adulthood gonadotropin-releasing hormone (GnRH) secretion, and mutations or deletions of GPR54 cause hypogonadotropic hypogonadism in humans and mice. Other reproductive roles for Kisspeptin–GPR54 signaling, including the regulation of developmental GnRH secretion or sexual behavior in adults, have not yet been explored. Using adult wild-type (WT) and GPR54 knock-out (KO) mice, we first tested whether Kisspeptin–GPR54 signaling is necessary for male and female sexual behaviors. We found that hormone-replaced gonadectomized GPR54 KO males and females displayed appropriate gender-specific adult sexual behaviors. Next, we examined whether GPR54 signaling is required for proper display of olfactory-mediated partner preference behavior. Testosterone-treated WT males preferred stimulus females rather than males, whereas similarly treated WT females and GPR54 KO males showed no preference for either sex. Because olfactory preference is sexually dimorphic and organized during development by androgens, we assessed whether GPR54 signaling is essential for sexual differentiation of other sexually dimorphic traits. Interestingly, adult testosterone-treated GPR54 KO males displayed “female-like” numbers of tyrosine hydroxylase-immunoreactive and Kiss1 mRNA-containing neurons in the anteroventral periventricular nucleus and likewise possessed fewer motoneurons in the spino-bulbocavernosus nucleus than did WT males. Our findings indicate that Kisspeptin–GPR54 signaling is not required for male or female copulatory behavior, provided there is appropriate adulthood hormone replacement. However, GPR54 is necessary for proper male-like development of several sexually dimorphic traits, likely by regulating GnRH-mediated androgen secretion during “critical windows” in perinatal development.
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minireview Kisspeptin neurons as central processors in the regulation of gonadotropin releasing hormone secretion
Endocrinology, 2006Co-Authors: Heather M Dungan, Donald K Clifton, Robert A SteinerAbstract:The Kiss1 gene encodes a family of peptides called Kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that Kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that Kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in...
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activation of gonadotropin releasing hormone neurons by Kisspeptin as a neuroendocrine switch for the onset of puberty
The Journal of Neuroscience, 2005Co-Authors: Michelle L Gottsch, Jeremy Troy Smith, Simina M Popa, Donald K Clifton, Robert A Steiner, Sonya K Jakawich, Allan E HerbisonAbstract:We examined the role of Kisspeptin and its receptor, the G-protein-coupled receptor GPR54, in governing the onset of puberty in the mouse. In the adult male and female mouse, Kisspeptin (10–100 nm) evoked a remarkably potent, long-lasting depolarization of >90% of gonadotropin-releasing hormone (GnRH)–green fluorescent protein neurons in situ . In contrast, in juvenile [postnatal day 8 (P8) to P19] and prepubertal (P26–P33) male mice, Kisspeptin activated only 27 and 44% of GnRH neurons, respectively. This developmental recruitment of GnRH neurons into a Kisspeptin-responsive pool was paralleled by an increase in the ability of centrally administered Kisspeptin to evoke luteinizing hormone secretion in vivo . To learn more about the mechanisms through which Kisspeptin–GPR54 signaling at the GnRH neuron may change over postnatal development, we performed quantitative in situ hybridization for Kisspeptin and GPR54 transcripts. Approximately 90% of GnRH neurons were found to express GPR54 mRNA in both juvenile and adult mice, without a detectable difference in the mRNA content between the age groups. In contrast, the expression of KiSS-1 mRNA increased dramatically across the transition from juvenile to adult life in the anteroventral periventricular nucleus (AVPV; p < 0.001). These results demonstrate that Kisspeptin exerts a potent depolarizing effect on the excitability of almost all adult GnRH neurons and that the responsiveness of GnRH neurons to Kisspeptin increases over postnatal development. Together, these observations suggest that activation of GnRH neurons by Kisspeptin at puberty reflects a dual process involving an increase in Kisspeptin input from the AVPV and a post-transcriptional change in GPR54 signaling within the GnRH neuron.
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A role for Kisspeptins in the regulation of gonadotropin secretion in the mouse.
Endocrinology, 2004Co-Authors: Michelle L Gottsch, Jeremy Troy Smith, Blake V Acohido, Simina M Popa, Matthew J Cunningham, Donald K Clifton, William F. Crowley, Stephanie B. Seminara, Robert A SteinerAbstract:Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that Kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of Kisspeptin-54 (metastin) and Kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the Kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of Kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of Kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in are...
Manuel Tenasempere - One of the best experts on this subject based on the ideXlab platform.
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discovery of potent Kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation
The Journal of Neuroscience, 2009Co-Authors: Antonia K Roseweir, Jeremy Troy Smith, Michelle L Gottsch, Alexander S. Kauffman, Manuel Tenasempere, Rafael Pineda, Kathryn A Guerriero, Kevin Morgan, Justyna Pieleckafortuna, Suzanne M MoenterAbstract:Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of Kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion, thus gating down-stream events supporting reproduction. We have developed Kisspeptin antagonists to facilitate the direct determination of the role of Kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of Kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of Kisspeptin in puberty onset. This analog also inhibited the Kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the postcastration rise in LH in sheep, rats, and mice, suggesting that Kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of Kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of Kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer.
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new frontiers in Kisspeptin gpr54 physiology as fundamental gatekeepers of reproductive function
Frontiers in Neuroendocrinology, 2008Co-Authors: L Pinilla, Manuel Tenasempere, E Aguilar, Carlos DieguezAbstract:Identification, in late 2003, of inactivating mutations of the G protein-coupled receptor GPR54 as causative factor for absence of puberty and hypogonadotropic hypogonadism in humans and mice was a major breakthrough in modern Neuroendocrinology, and drew considerable interest on the characterization of the roles of this receptor and its ligands (Kisspeptins, encoded by the KiSS-1 gene) in the physiological control of essential facets of reproduction. After 3 years of intense research activity, Kisspeptins are universally recognized as essential activators of the gonadotropic axis, with key roles in puberty onset and the control of gonadotropin secretion. While these fundamental functions are now well settled, novel aspects of Kisspeptin/GPR54 physiology have emerged, including their involvement in the neuroendocrine control of ovulation and the metabolic gating of reproductive function. In addition, the 'comparative endocrinology' of this system has begun to be explored recently. These facets of Kisspeptin/GPR54 function, as fundamental gatekeepers of reproduction, will be comprehensively reviewed herein.
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direct pituitary effects of Kisspeptin activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion
Journal of Neuroendocrinology, 2007Co-Authors: Ester Gutierrezpascual, Antonio J Martinezfuentes, L Pinilla, Manuel Tenasempere, Maria M Malagon, Justo P CastanoAbstract:Recent, compelling evidence indicates that Kisspeptins, the products of KiSS-1 gene, and their receptor GPR54, represent key elements in the neuroendocrine control of reproduction, and that they act primarily by regulating gonadotrophin-releasing hormone (GnRH) secretion at the hypothalamus. Conversely, and despite earlier reports showing GPR54 expression in the pituitary, the potential physiological roles of Kisspeptins at this gland have remained elusive. To clarify this issue, cultures of rat pituitary cells were used to evaluate expression of KiSS-1 and GPR54, and to monitor the ability of Kisspeptin-10 to stimulate Ca 2+ responses in gonadotrophs and to elicit luteinising hormone (LH) secretion in vitro. The results obtained show that both GPR54 and KiSS-1 are expressed in the pituitary of peripubertal male and female rats. Moreover, kiss-peptin-10 induced a rise in free cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in approximately 10% of male rat pituitary cells. Intriguingly, Kisspeptin-responsive cells included not only gonadotrophs, in which a 62.8 ± 16.0% [Ca 2+ ] i rise was observed, but also somatotrophs, wherein Kisspeptin induced a 60.3 ± 5.5% [Ca 2+ ] i increase. Accordingly, challenge of dispersed pituitary cells with increasing Kisspeptin-10 concentrations induced dose-related LH and growth hormone (GH) secretory responses, which were nevertheless of lower magnitude than those evoked by the primary regulators GnRH and GH-releasing hormone, respectively. In particular, 10 -8 M Kisspeptin caused maximal increases in LH release (218.7 ± 23.6% and 180.4 ± 7.2% in male and female rat pituitary cells, respectively), and also stimulated maximally GH secretion (181.9 ± 14.9% and 260.2 ± 15.9% in male and female rat pituitary cells, respectively). Additionally, moderate summation of Kisspeptin- and GnRH-induced LH responses was observed after short-term incubation of male rat pituitary cells. In conclusion, our results provide unequivocal evidence that Kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action. The precise relevance and underlying mechanisms of this potential new actions of Kisspeptins (i.e. the direct modulation of gonadotrophic and somato-trophic axis at the pituitary) deserve further analysis.
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gpr54 and Kisspeptin in reproduction
Human Reproduction Update, 2006Co-Authors: Manuel TenasempereAbstract:Kisspeptins, the peptide products of the KiSS-1 gene, were identified in 2001 as natural ligands of the previously orphan G protein-coupled receptor, GPR54. They include, among others, metastin and Kisspeptin-10. The known biological functions of Kisspeptins were initially restricted to their ability to suppress tumour metastasis, hence the name of metastin. However, in late 2003, two groups independently reported that loss-of-function mutations of the GPR54 gene are linked to absence of puberty onset and hypogonadotrophic hypogonadism in humans—a phenotype that was reproduced in GPR54-null mice. Those seminal observations revealed a totally unexpected, fundamental role of the KiSS-1/GPR54 system in control of puberty and reproductive function and boosted an extraordinary interest for the characterization of these novel facets of Kisspeptin physiology. Indeed, in the last 2 years, metastin and Kisspeptin-10 have been demonstrated as very potent stimulators of the gonadotrophic axis, in a number of species and through different routes of administration. In addition, the hypothalamic KiSS-1/GPR54 system has been proven as an essential gatekeeper of GnRH neurons, involved in their activation at puberty and their regulation by gonadal steroids and (probably) metabolic factors. This review comprehensively examines the experimental evidence obtained to date supporting a pivotal role of Kisspeptins and GPR54 in the control of reproduction.
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expression of hypothalamic kiss 1 system and rescue of defective gonadotropic responses by Kisspeptin in streptozotocin induced diabetic male rats
Diabetes, 2006Co-Authors: Juan M Castellano, L Pinilla, E Aguilar, Carlos Dieguez, E Vigo, Victor M Navarro, R Fernandezfernandez, Rafael Pineda, Manuel TenasempereAbstract:Hypogonadotropism is a common feature of uncontrolled diabetes, for which the ultimate mechanism remains to be elucidated. Kisspeptins, ligands of G protein–coupled receptor 54 (GPR54) encoded by the KiSS-1 gene, have recently emerged as major gatekeepers of the gonadotropic axis. Alteration in the hypothalamic KiSS-1 system has been reported in adverse metabolic conditions linked to suppressed gonadotropins, such as undernutrition. However, its potential contribution to defective gonadotropin secretion in diabetes has not been evaluated. We report herein analyses of luteinizing hormone (LH) responses to Kisspeptin and hypothalamic expression of the KiSS-1 gene in streptozotocin (STZ)-induced diabetic male rats. In addition, functional studies involving Kisspeptin replacement or continuous administration of leptin and insulin to diabetic male rats are presented. Kisspeptin administration evoked robust LH and testosterone bursts and enhanced postgonadectomy LH concentrations, despite prevailing attenuation of gonadotropic axis in diabetic animals. In addition, hypothalamic KiSS-1 mRNA levels were unambiguously decreased in diabetic male rats, and the postorchidectomy rise in KiSS-1 mRNA was severely blunted. Repeated administration of Kisspeptin to diabetic rats evoked persistent LH and testosterone responses and partially rescued prostate and testis weights. In addition, central infusion of leptin, but not insulin, was sufficient to normalize hypothalamic KiSS-1 mRNA levels, as well as LH and testosterone concentrations. In summary, we provide evidence for altered expression of the hypothalamic KiSS-1 system in a model of uncontrolled diabetes. This observation, together with the ability of exogenous Kisspeptin to rescue defective LH responses in diabetic rats, unravel the physiopathological implication, and potential therapeutic intervention, of the KiSS-1 system in altered gonadotropin secretion of type 1 diabetes.
Jeremy Troy Smith - One of the best experts on this subject based on the ideXlab platform.
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Kisspeptin Signaling in Reproductive Biology - Kisspeptin signaling in reproductive biology
Advances in Experimental Medicine and Biology, 2020Co-Authors: Alexander S. Kauffman, Jeremy Troy SmithAbstract:Part One: Kisspeptin Signaling in vivo and in vitro.- Kisspeptin: Past, Present and Prologue.- Structure, Synthesis, and Phylogeny of Kisspeptin and its Receptor.- Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects.- The Effects of Kisspeptin on Gonadotropin Release in Non-Human Mammals.- Effects of Kisspeptin on Hormone Secretion in Humans.- Kisspeptin Excitation of GnRH Neurons.- Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations.- Kisspeptin Antagonists.- Kisspeptin and Clinical Disorders.- Beyond the GnRH Axis: Kisspeptin Regulation of the Oxytocin System in Pregnancy and Lactation.- Part Two: Development and Regulation of Kisspeptin Neurons.- The Development of Kisspeptin Circuits in the Mammalian Brain.- Kisspeptin and Puberty in Mammals.- Sex Steroid Regulation of Kisspeptin Circuits.- Kisspeptin and GnRH Pulse Generation.- Interactions between Kisspeptins and Neurokinin B.- Electrophysiology of Kisspeptin Neurons.- Metabolic Regulation of Kisspeptin.- Circadian Regulation of Kisspeptin in Female Reproductive Functioning.- Kisspeptin and Seasonality of Reproduction.- Stress Regulation of Kisspeptin in the Modulation of Reproductive Function.- Effects of Environmental Endocrine Disruptors and Phytoestrogens on the Kisspeptin System.- Model Systems for Studying Kisspeptin Signaling: Mice and Cells.- Index.
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The role of Kisspeptin neurons in reproduction and metabolism.
Journal of Endocrinology, 2018Co-Authors: Campbell J L Harter, Georgia S Kavanagh, Jeremy Troy SmithAbstract:Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin is produced by two major populations of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC). These neurons project to and activate gonadotrophin-releasing hormone (GnRH) neurons (acting via the Kisspeptin receptor, Kiss1r) in the hypothalamus and stimulate the secretion of GnRH. Gonadal sex steroids stimulate Kisspeptin neurons in the RP3V, but inhibit Kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC Kisspeptin neurons act as the GnRH pulse generator. Due to Kisspeptin's profound effect on the HPG axis, a focus of recent research has been on afferent inputs to Kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition. Alternatively, evidence is building for a direct role for Kisspeptin in regulating energy balance and metabolism. Kiss1r-knockout (KO) mice exhibit increased adiposity and reduced energy expenditure. Although the mechanisms underlying these observations are currently unknown, Kiss1r is expressed in adipose tissue and potentially brown adipose tissue (BAT) and Kiss1rKO mice exhibit reduced energy expenditure. Recent studies are now looking at the effects of Kisspeptin signalling on behaviour, with clinical evidence emerging of Kisspeptin affecting sexual behaviour, further investigation of potential neuronal pathways are warranted.
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Stimulation of growth hormone by Kisspeptin antagonists in ewes
Journal of Endocrinology, 2018Co-Authors: Jeremy Troy Smith, Antonia K Roseweir, Iain J Clarke, Michael Millar, Robert P MillarAbstract:Kisspeptin signalling is indispensable for fertility, stimulating gonadotropin- releasing hormone (GnRH) secretion and mediating gonadal steroid feedback on GnRH neurons. Moreover, Kisspeptin neurons have been implicated in other non-reproductive neuroendocrine roles. Kisspeptin appears to also regulate growth hormone secretion but much of the data appear contradictory. We sought to clarify a potential role of Kisspeptin in GH regulation by examining the effect of Kisspeptin antagonists on growth hormone (GH) secretion in ewes under various physiological conditions. Our data show clear and robust increases in GH secretion following lateral ventricle or third ventricle infusion of Kisspeptin antagonists p-234 and p-271 in either ovariectomised or anestrous ewes. Central infusion of Kisspeptin-10 had no effect on GH secretion. To determine the level at which Kisspeptin may influence GH secretion we examined expression of the cognate Kisspeptin receptor, GPR54, in pituitary cells and showed by immunocytochemistry that the majority of somatotropes express GPR54 while expression was largely negative in other pituitary cells. Overall, we have demonstrated that blocking Kisspeptin signalling by antagonists stimulates GH secretion in ewes and that this is likely mediated by inhibiting endogenous Kisspeptin activation of GPR54 expressed on somatotropes. The findings suggest that endogenous Kisspeptin inhibits growth hormone secretion through GPR54 expressed on somatotropes.
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Kisspeptin and energy balance in reproduction
Reproduction, 2014Co-Authors: Julie-ann P De Bond, Jeremy Troy SmithAbstract:Kisspeptin is vital for the neuroendocrine regulation of GNRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GNRH neurons. This pathway is likely to mediate the well-established link between energy balance and reproductive function. Thus, in states of severely altered energy balance (either negative or positive), fertility is compromised, as is Kiss1 expression in the arcuate nucleus. A number of metabolic modulators have been proposed as regulators of Kisspeptin neurons including leptin, ghrelin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY). Whether these regulate Kisspeptin neurons directly or indirectly will be discussed. Moreover, whether the stimulatory role of leptin on reproduction is mediated by Kisspeptin directly will be questioned. Furthermore, in addition to being expressed in GNRH neurons, the Kisspeptin receptor (Kiss1r) is also expressed in other areas of the brain, as well as in the periphery, suggesting alternative roles for Kisspeptin signaling outside of reproduction. Interestingly, Kisspeptin neurons are anatomically linked to, and can directly excite, anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, Kisspeptin may have a direct role in regulating energy balance. Although data from Kiss1r knockout and WT mice found no differences in body weight, recent data indicate that Kisspeptin may still play a role in food intake and glucose homeostasis. Thus, in addition to regulating reproduction, and mediating the effect of energy balance on reproductive function, Kisspeptin signaling may also be a direct regulator of metabolism. Reproduction (2014) 147 R53–R63 Kisspeptin governs puberty onset and reproduction Kisspeptin is a hypothalamic neuropeptide that drives fertility by stimulating gonadotropin-releasing hormone (GNRH) neurons (Gottsch et al. 2004, Han et al. 2005). A product of the KISS1 gene, Kisspeptin, is cleaved from an initial 145 amino acid precursor to a 54 amino acid peptide in humans (Kotani et al. 2001, Ohtaki et al. 2001) and a 52 amino acid peptide in mice (Terao et al. 2004). In humans, smaller isoforms of 14 and 13 amino acids have also been isolated, each sharing the common C-terminal sequence (Kotani et al. 2001, Ohtaki et al. 2001). Kisspeptin binds to the once orphaned G-proteincoupled receptor-54 (Kotani et al. 2001), now commonly referred to as Kiss1r (Gottsch et al. 2009). Two independent research groups discovered the essential role of Kisspeptin in reproduction almost simultaneously in 2003, when Kiss1r mutations were isolated in cases of idiopathic hypogonadotropic hypergonadism (de Roux et al. 2003, Seminara et al. 2003). Seminara et al. (2003) were also the first to examine Kiss1r null mice, which shared the infertility and had no other discernible phenotype. It is now universally accepted that Kisspeptin is fundamental to GNRH-driven fertility and the key pieces of evidence for q 2014 Society for Reproduction and Fertility ISSN 1470–1626 (paper) 1741–7899 (online) this include the following: i) the stimulatory effect of Kisspeptin is blocked by GNRH antagonists (Gottsch et al. 2004, Irwig et al. 2004, Matsui et al. 2004, Shahab et al. 2005); ii) injections of Kisspeptin directly in to the vicinity of GNRH neuron stimulate luteinizing hormone (LH) secretion (Patterson et al. 2006); iii) Kisspeptin activates GNRH neurons in vivo (Irwig et al. 2004, Matsui et al. 2004) and in vitro (Han et al. 2005, Pielecka-Fortuna et al. 2008); iv) Kisspeptin immunoreactive fibers appose GNRH neuron cell bodies (Kinoshita et al. 2005, Clarkson & Herbison 2006, Smith et al. 2008) and their terminals within the median eminence (Smith et al. 2011); v) Kisspeptin stimulates GNRH release into the portal circulation of sheep (Smith et al. 2011) and the isolated mediobasal hypothalamus (d’Anglemont de Tassigny et al. 2008); and finally vi) almost all GNRH neurons express Kiss1r (Irwig et al. 2004, Han et al. 2005, Smith et al. 2009). Importantly, the effects of Kisspeptin are absent in Kiss1r knockout (KO) mice, showing specificity to this receptor (Messager et al. 2005, Dungan et al. 2007, Kauffman et al. 2007). It is worthy to note that using a genetic ablation approach, the importance of the Kisspeptin system in mice has been challenged. Mice with ablated Kisspeptin neurons presented with normal fertility DOI: 10.1530/REP-13-0509 Online version via www.reproduction-online.org R54 J-A P De Bond and J T Smith (Mayer & Boehm 2011). However, it is questionable whether a complete loss of Kisspeptin cells was achieved. It is likely that this result reflects redundancy in Kisspeptin neurons and signaling as genetically targeted mice with 50 and 95% reductions in Kiss1 transcript still maintain, albeit impaired in females, fertility (Popa et al. 2013). In addition, the DBA/2J mouse strain possess less than one-tenth the level of Kiss1 mRNA in the brain than the C57BL/6 mice (Quennell et al. 2011), yet are fertile. Thus, these data may highlight the importance of Kisspeptin in reproduction, in that it is synthesized in excess to ensure reproductive success. One of the primary functions of Kisspeptin appears to be as an interneuronal bridge between systemic levels of sex steroids and GNRH neuron regulation (Smith 2013; Fig. 1). In rodents, Kisspeptin-producing cells are found in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) (Smith 2013). In sheep, Kisspeptin neurons are located in the dorsolateral region of the preoptic area (POA) (perhaps a homologous population to the rodent AVPV) and the ARC (Estrada et al. 2006, Smith et al. 2007), and estrogen regulation of Kisspeptin has been extensively studied in these regions in both rodents and sheep (Smith 2013). Both neuronal populations are important in the generation of estrogenpositive feedback and sex steroid-negative feedback signals to GNRH neurons. The former, critical for the GNRH/LH surge and ovulation in females and the latter, involved in the tonic/pulsatile regulation of GNRH secretion in both sexes (Simerly 2002, Herbison 2008). Specifically, sex steroids robustly regulate Kisspeptin neurons and those in the ARC forward signals applicable to negative feedback regulation of GNRH in mice (Smith et al. 2005a, 2005b). In the female rodent,
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Sex Steroid Regulation of Kisspeptin Circuits
Advances in Experimental Medicine and Biology, 2013Co-Authors: Jeremy Troy SmithAbstract:Kisspeptin cells appear to be the “missing link,” bridging the divide between levels of gonadal steroids and feedback control of gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin neurons are important in the generation of both sex steroid negative and estrogen positive feedback signals to GnRH neurons, the former being involved in the tonic regulation of GnRH secretion in males and females and the latter governing the preovulatory GnRH/luteinizing hormone (LH) surge in females. In rodents, Kisspeptin-producing cells populate the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), and estrogen regulation of Kisspeptin has been extensively studied in these regions. Kisspeptin cells in the ARC appear to receive and forward signals applicable to negative feedback regulation of GnRH. In the female rodent AVPV, Kisspeptin cells are important for positive feedback regulation of GnRH and the preovulatory LH surge. In sheep and primates, a rostral population of Kisspeptin cells is located in the dorsolateral preoptic area (POA) as well as the ARC. Initial studies showed Kisspeptin cells in the latter were involved in both the positive and negative feedback regulation of GnRH. Interestingly, further studies now suggest that Kisspeptin cells in the ovine POA may also play an important role in generating estrogen positive feedback. This chapter discusses the current consensus knowledge regarding the interaction between sex steroids and Kisspeptin neurons in mammals.
Waljit S. Dhillo - One of the best experts on this subject based on the ideXlab platform.
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Kisspeptin as a therapeutic target in reproduction
Expert Opinion on Therapeutic Targets, 2015Co-Authors: Lisa Yang, Waljit S. DhilloAbstract:ABSTRACTIntroduction: Kisspeptins are a family of neuropeptides whose identification has become one of the biggest discoveries in reproductive endocrinology during the past decade. Kisspeptins act upstream of GnRH as high-level mediators of the reproductive axis.Areas covered: The authors performed a search of all publications on Kisspeptin since its discovery in 1996. A full appraisal of the expanding literature concerning Kisspeptin is beyond the scope of this review. This article therefore aims to cover the principle human studies outlining Kisspeptin action in human physiology and to discuss the key findings, describing Kisspeptin’s potential as a therapeutic target in human reproduction.Expert opinion: The identification of the Kisspeptin signaling pathway has greatly advanced the study of reproductive endocrinology. Building on a large body of animal data, a growing number of human studies have shown that exogenous Kisspeptin can stimulate physiological gonadotropin responses in both healthy subject...
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comprehensive review on Kisspeptin and its role in reproductive disorders
Endocrinology and Metabolism, 2015Co-Authors: Holly Clarke, Waljit S. Dhillo, Channa N JayasenaAbstract:Kisspeptin has recently emerged as a key regulator of the mammalian reproductive axis. It is known that Kisspeptin, acting centrally via the Kisspeptin receptor, stimulates secretion of gonadotrophin releasing hormone (GnRH). Loss of Kisspeptin signaling causes hypogonadotrophic hypogonadism in humans and other mammals. Kisspeptin interacts with other neuropeptides such as neurokinin B and dynorphin, to regulate GnRH pulse generation. In addition, a growing body of evidence suggests that Kisspeptin signaling be regulated by nutritional status and stress. Kisspeptin may also represent a novel potential therapeutic target in the treatment of fertility disorders. Early human studies suggest that peripheral exogenous Kisspeptin administration stimulates gonadotrophin release in healthy adults and in patients with certain forms of infertility. This review aims to concisely summarize what is known about Kisspeptin as a regulator of reproductive function, and provide an update on recent advances within this field.
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Kisspeptin and fertility
Journal of Endocrinology, 2011Co-Authors: Saira Hameed, Channa N Jayasena, Waljit S. DhilloAbstract:The Kisspeptins are af amilyof peptide hormones, which in recent years have been shown to play a critical role in the regulation of the hypothalamic–pituitary–gonadal axis, thus in turn influencing fertility and reproduction. This review examines the physiological role of Kisspeptin and the Kisspeptin receptor in the control of gonadotrophin and gonadal steroid hormone secretion and the implications of these findings with respect to fertility. In addition, the potential therapeutic use of Kisspeptin in the treatment of reproductive disorders will be examined.
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Kisspeptin: A Critical Regulator of Puberty and Reproductive Function
Current Drug Targets, 2010Co-Authors: Waljit S. DhilloAbstract:Kisspeptin has emerged as a critical player in the initiation of puberty and reproductive function. In humans, inactivating mutations of the Kisspeptin receptor result in hypogonadotrophic hypogonadism and Kisspeptin receptor activating mutations cause precocious puberty. Kisspeptin potently stimulates the release of gonadotrophins predominantly through the release of gonadotrophin-releasing hormone (GnRH). Here we review the data from animal and human studies exploring the role of Kisspeptin in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin signalling presents a novel target for therapeutic manipulation of the HPG axis.
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the Kisspeptin system of the human hypothalamus sexual dimorphism and relationship with gonadotropin releasing hormone and neurokinin b neurons
European Journal of Neuroscience, 2010Co-Authors: Erik Hrabovszky, M. A. Ghatei, Waljit S. Dhillo, Alain Caraty, Philippe Ciofi, Barbara Vida, M Horvath, Eva Keller, S R Bloom, Zsolt LipositsAbstract:Kisspeptin signaling via the Kisspeptin receptor G-protein-coupled receptor-54 plays a fundamental role in the onset of puberty and the regulation of mammalian reproduction. In this immunocytochemical study we addressed the (i) topography, (ii) sexual dimorphism, (iii) relationship to gonadotropin-releasing hormone (GnRH) neurons and (iv) neurokinin B content of Kisspeptin-immunoreactive hypothalamic neurons in human autopsy samples. In females, Kisspeptin-immunoreactive axons formed a dense periventricular plexus and profusely innervated capillary vessels in the infundibular stalk. Most immunolabeled somata occurred in the infundibular nucleus. Many cells were also embedded in the periventricular fiber plexus. Rostrally, they formed a prominent periventricular cell mass (magnocellular paraventricular nucleus). Robust sex differences were noticed in that fibers and somata were significantly less numerous in male individuals. In dual-immunolabeled specimens, fine Kisspeptin-immunoreactive axon varicosities formed axo-somatic, axo-dendritic and axo-axonal contacts with GnRH neurons. Dual-immunofluorescent studies established that 77% of Kisspeptin-immunoreactive cells in the infundibular nucleus synthesize the tachykinin peptide neurokinin B, which is known to play crucial role in human fertility; 56 and 17% of Kisspeptin fibers in the infundibular and periventricular nuclei, respectively, contained neurokinin B immunoreactivity. Site-specific co-localization patterns implied that Kisspeptin neurons in the infundibular nucleus and elsewhere contributed differentially to these plexuses. This study describes the distribution and robust sexual dimorphism of Kisspeptin-immunoreactive elements in human hypothalami, reveals neuronal contacts between Kisspeptin-immunoreactive fibers and GnRH cells, and demonstrates co-synthesis of Kisspeptins and neurokinin B in the infundibular nucleus. The neuroanatomical information will contribute to our understanding of central mechanisms whereby Kisspeptins regulate human fertility.
