Maturation of kisspeptinergic neurons coincides with puberty onset in male rats

Bentsen, Agnete H.; Ansel, Laura; Simonneaux, Valérie; Tena‐Sempere, Manuel; Juul, Anders; Mikkelsen, Jens D.

doi:10.1016/j.peptides.2009.11.017

Cited by 57 publications

(65 citation statements)

References 53 publications

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“…Firstly, inactivating mutations in KISS1R/Kiss1r, (106)(107)(108) and KISS1/Kiss1 (64,111) led to HH and pubertal failure. Secondly, animal studies demonstrated an increase in Kiss1 and Kiss1r in the AVPV and/or ARC at puberty; (9,43,52,62,(112)(113)(114)(115)(116)(117) more kisspeptin neurons also project to GnRH neurons. (43,(118)(119)(120) Thirdly, GnRH response to kisspeptins increases after puberty, which is secondary to improved signalling efficiency rather than increased receptor density (9) (Fig.…”

Section: Reproductive Function and Pubertymentioning

confidence: 97%

Kisspeptin signalling and its roles in humans

Tng

2015

smedj

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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.

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Section: Reproductive Function and Pubertymentioning

confidence: 97%

Kisspeptin signalling and its roles in humans

Tng

2015

smedj

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“…The sections were then incubated at 4°C for 24 h with a purified rabbit antiserum against mouse kisspeptin-52 (code JLV-1) diluted 1:200 in 0.01 M PBS with 0.3% Triton X-100 and 1% BSA. This antiserum was developed and fully validated in-house by J. D. Mikkelsen to recognize the longer endogenous form of kisspeptin-52 without showing any detectable cross-reactivity with RFamide-related peptide (3,21). After incubation in primary antiserum, IR was detected by means of the avidin-biotin method using diaminobenzidine as chromagen.…”

Section: Animals and Reagentsmentioning

confidence: 99%

Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects

Castellano

Bentsen

Martín‐Romero

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Tena-Sempere M. Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects. Am J Physiol Endocrinol Metab 299: E54 -E61, 2010. First published April 20, 2010 doi:10.1152/ajpendo.00081.2010.-Severe inflammatory challenges are frequently coupled to decreased food intake and disruption of reproductive function, the latter via deregulation of different signaling pathways that impinge onto GnRH neurons. Recently, the hypothalamic Kiss1 system, a major gatekeeper of GnRH function, was suggested as potential target for transmitting immune-mediated repression of the gonadotropic axis during acute inflammation, and yet key facets of such a phenomenon remain ill defined. Using lipopolysaccharide S (LPS)-treated male rats as model of inflammation, we document herein the pattern of hypothalamic kisspeptin immunoreactivity (IR) and hormonal responses to kisspeptin during the acute inflammatory phase. LPS injections induced a dramatic but transient drop of serum LH and testosterone levels. Suppression of gonadotropic function was associated with a significant decrease in kisspeptin-IR in the arcuate nucleus (ARC) that was not observed under conditions of metabolic stress induced by 48-h fasting. In addition, absolute responses to kisspeptin-10 (Kp-10), in terms of LH and testosterone secretion, were significantly attenuated in LPS-treated males that also displayed a decrease in food intake and body weight. Yet pair-fed males did not show similar alterations in LH and testosterone secretory responses to Kp-10, whose magnitude was preserved, if not augmented, during food restriction. In summary, our data document the impact of acute inflammation on kisspeptin content at the ARC as key center for the neuroendocrine control of reproduction. Our results also suggest that suppressed gonadotropic function following inflammatory challenges might involve a reduction in absolute responsiveness to kisspeptin that is independent of the anorectic effects of inflammation.Kiss1/kisspeptins; gonadotropin-releasing hormone; gonadotropins; lipopolysaccharide S IMMUNE/INFLAMMATORY CHALLENGES, such as those associated with severe bacterial infections, are commonly coupled with transient suppression of dispensable functions for individual survival, such as reproduction. Among a plethora of biological responses, administration of lipopolysaccharide S (LPS), a glycolipid of gram-negative bacteria, has been shown to disrupt puberty onset and gonadotropic function through deregulation of an array of signaling pathways, including different proinflammatory cytokines (IL-1, IL-6, TNF␣), growth factors, neurotransmitters (catecholamines, ␥-aminobutyric acid), and neuropeptides (corticotropin-releasing factor, arginine vasopressin, opioids) (1,10,16,28,33,35,37,39). However, although compelling evidence suggests that the above factors are variably involved in the suppression of the gonadotropinreleasing hormone (GnRH)/LH system by bacterial endotoxin (37,...

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“…Kisspeptin and GPR54 are important for puberty and subsequent fertility; mutations or targeted deletions in the genes encoding kisspeptin or GPR54 cause profound hypogonadotropic hypogonadism, failure to undergo puberty and infertility [9,10,11,12]. Kisspeptin released from presynaptic neurons acts on GnRH neurons directly, and indirectly (transsynaptically), to produce long-lasting (20–30 min) depolarization and increased action potential firing [13,14,15,16,17,18,19,20,21] along with increased cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) [17,22,23] required for the increased GnRH secretion. However, the mechanism by which kisspeptin increases [Ca 2+ ] i in GnRH neurons has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Kisspeptin Inhibits High-Voltage Activated Ca<sup>2+</sup> Channels in GnRH Neurons via Multiple Ca<sup>2+</sup> Influx and Release Pathways

Zhang

Spergel

2012

Neuroendocrinology

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Kisspeptin plays an important role in puberty and subsequent fertility by activating its receptor, G-protein-coupled receptor 54 (GPR54), and increasing cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i) and gonadotropin-releasing hormone (GnRH) secretion in GnRH neurons. Yet the mechanism by which kisspeptin increases [Ca²⁺]_i in GnRH neurons remains to be fully elucidated. In other neurons, voltage-gated Ca²⁺ channel (VGCC) activity has been shown to be inversely related to [Ca²⁺]_i. We used whole-cell patch-clamp recording to examine the effects of kisspeptin-10 (KP-10) on VGCC activity evoked by step depolarizations in GnRH neurons in brain slices from pubertal male GnRH-green fluorescent protein transgenic mice. Prolonged (>30 s) KP-10 application inhibited Ca²⁺ currents. The GPR54 antagonist peptide 234, chelation of intracellular Ca²⁺ by 1,2-bis(2-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid, substitution of Ba²⁺ for Ca²⁺, the calmodulin antagonists calmidazolium and trifluoperazine, the phospholipase C inhibitor edelfosine, the canonical transient receptor potential (TRPC) channel and inositol 1,4,5-trisphosphate receptor (IP₃R) antagonist 2-APB, the TRPC channel antagonist BTP2 and the endoplasmic reticulum Ca²⁺-ATPase blocker cyclopiazonic acid each prevented inhibition. The IP₃R antagonists caffeine (10 µM), heparin and intracellular 2-APB prevented inhibition to a lesser extent. The ryanodine receptor (RyR) antagonists ryanodine and dantrolene prevented inhibition, and the RyR agonist caffeine (30 mM) mimicked the effects of KP-10 on Ca²⁺ currents. Our results suggest that kisspeptin induces Ca²⁺ influx through TRPC channels and Ca²⁺ release via IP₃Rs and RyRs, and that this is followed by Ca²⁺/CaM-dependent inhibition of VGCCs.

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Maturation of kisspeptinergic neurons coincides with puberty onset in male rats

Cited by 57 publications

References 53 publications

Kisspeptin signalling and its roles in humans

Kisspeptin signalling and its roles in humans

Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects

Kisspeptin Inhibits High-Voltage Activated Ca<sup>2+</sup> Channels in GnRH Neurons via Multiple Ca<sup>2+</sup> Influx and Release Pathways

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