Context Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons). Objective We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally-restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood brain barrier) and impedes their down-stream effects. Design Case/control. Setting Academic medical center. Participants Mice. Interventions Administration of peripherally-restricted kappa receptor agonists and frequent blood sampling to determine hormone release, and body temperature. Main Outcome Measures LH pulse parameters and body temperature. Results First, chronic administration of a PRKA to OVX mice with experimentally-induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity. Conclusion The inhibition of Kiss1 neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.
The alternation of the stimulatory action of the tachykinin neurokinin B (NKB) and the inhibitory action of dynorphin within arcuate (ARH) Kiss1 neurons has been proposed as the mechanism behind the generation of GnRH pulses through the pulsatile release of kisspeptin. However, we have recently documented that GnRH pulses still exist in gonadectomized mice in the absence of tachykinin signaling. Here, we document an increase in basal frequency and amplitude of LH pulses in intact male mice deficient in substance P (SP), neurokinin A (NKA) signaling (Tac1KO) and NKB signaling (Tac2KO and Tacr3KO). Moreover, we offer evidence that a single bolus of the NKB receptor agonist senktide to gonad intact WT males increases the basal release of LH without changing its frequency. Altogether, these data support the dispensable role of the individual tachykinin systems in the generation of LH pulses. Moreover, the increased activity of the GnRH pulse generator in intact KO male mice suggests the existence of compensation by additional mechanisms in the generation of kisspeptin/GnRH pulses.
Reproduction, controlled by the excitatory action of the neuropeptide kisspeptin, is an energy costly function for the organism and, therefore, it is tightly regulated by metabolic factors. Among those, hypothalamic melanocortins are essential in the control of metabolism. Inactivating mutations in the proopiomelanocortin ( Pomc ) gene or melanocortin receptor 4 (Mc4r) cause severe obesity and subfertility in humans and mice. However, whether the reproductive impairment is a direct consequence of the lack of melanocortin signaling, or indirect resulting from the obesity phenotype, remains unknown. α-MSH (derived from Pomc ) stimulates LH release and this action has been shown to be mediated by Kiss1 neurons. We evaluated the expression of Mc4r in Kiss1 neurons, and using dual fluorescence in situ hybridization (RNAscope), we showed that Kiss1 neurons of the arcuate nucleus (Kiss1 ARC ) and the anteroventral periventricular/periventricular nucleus (Kiss1 AVPV/PeN ) express Mc4r . Mc4r colocalized with 84% of Kiss1 ARC and with 74% of Kiss1 AVPV/PeN , suggesting that Kiss1 neurons are a direct target of melanocortins. In order to evaluate the involvement of Kiss1 neurons in the reproductive role of melanocortins, we ablated Mc4r specifically from Kiss1 neurons by generating a specific Kiss1-Mc4rKO ( Kiss1 -cre + / Mc4r -lox +/+ ) mouse line. We found that Kiss1-Mc4rKO females exhibit disrupted estrous cycles with prolonged diestrous phases and delayed puberty onset compared to their control littermates, without developing obesity during the time of the study. The reproductive phenotype of Kiss1-Mc4rKO males was not affected. When central injections of an Mc4r selective agonist were performed on Kiss1-Mc4rKO intact males and their control littermates, LH levels were significantly increased to the same extend in both groups at 15 min post-injections, suggesting that, in the male, α-MSH controls LH levels through a Kiss1 neuron independent mechanism. Taken together, these results support a direct role of melanocortins on Kiss1 neurons in the control of GnRH release in female mice. Overall, understanding the neuroendocrine mechanisms underlying the metabolic regulation of reproduction will help improve the fertility rates in patients affected by metabolic disturbances. Keywords: Kisspeptin, α-MSH, Melanocortins, Mc4r, Reproduction
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.