Increased Neurokinin B (Tac2) Expression in the Mouse Arcuate Nucleus Is an Early Marker of Pubertal Onset with Differential Sensitivity to Sex Steroid-Negative Feedback than Kiss1

Abstract

At puberty, neurokinin B (NKB) and kisspeptin (Kiss1) may help to amplify GnRH secretion, but their precise roles remain ambiguous. We tested the hypothesis that NKB and Kiss1 are induced as a function of pubertal development, independently of the prevailing sex steroid milieu. We found that levels of Kiss1 mRNA in the arcuate nucleus (ARC) are increased prior to the age of puberty in GnRH/sex steroid-deficient hpg mice, yet levels of Kiss1 mRNA in wild-type mice remained constant, suggesting that sex steroids exert a negative feedback effect on Kiss1 expression early in development and across puberty. In contrast, levels of Tac2 mRNA, encoding NKB, and its receptor (NK3R; encoded by Tacr3) increased as a function of puberty in both wild-type and hpg mice, suggesting that during development Tac2 is less sensitive to sex steroid-dependent negative feedback than Kiss1. To compare the relative responsiveness of Tac2 and Kiss1 to the negative feedback effects of gonadal steroids, we examined the effect of estradiol (E(2)) on Tac2 and Kiss1 mRNA and found that Kiss1 gene expression was more sensitive than Tac2 to E(2)-induced inhibition at both juvenile and adult ages. This differential estrogen sensitivity was tested in vivo by the administration of E(2). Low levels of E(2) significantly suppressed Kiss1 expression in the ARC, whereas Tac2 suppression required higher E(2) levels, supporting differential sensitivity to E(2). Finally, to determine whether inhibition of NKB/NK3R signaling would block the onset of puberty, we administered an NK3R antagonist to prepubertal (before postnatal d 30) females and found no effect on markers of pubertal onset in either WT or hpg mice. These results indicate that the expression of Tac2 and Tacr3 in the ARC are markers of pubertal activation but that increased NKB/NK3R signaling alone is insufficient to trigger the onset of puberty in the mouse.

Tachykinin: recent developments and novel roles in health and disease

“…The expression of Kiss1 mRNA encoding for kisspeptin increased in the ARC prior to the onset of puberty in GnRH/ sex steroid-deficient hpg mice, whereas Tac3 encoding NKB increased at puberty in both wild-type and hpg mice (141), suggesting that neurons involved in negative feedback regulation have different sensitivities to sex steroid. Indeed, E 2 administration revealed that Kiss1 gene expression was more sensitive than Tac2 expression in the ARC (141). However, the prepubertal treatment of wild-type and hpg mice with an NK3R antagonist did not alter the onset of puberty.…”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…As a whole, the available evidence suggests that the NKB (auto)regulatory system of KNDy neurons, as described earlier for sexually mature animals, is operative and likely to play a role during pubertal maturation in rodents. Indeed, comparison of expression profiles of NKB and Kiss1 genes in the hypothalamus of female rats during postnatal development would suggest that the rise of NKB expression anticipates the elevation of Kiss1 mRNA levels, a phenomenon that has been recently documented in the mouse (43), and whose functional implications are yet to be elucidated. In the same vein, a modulatory role of NKB signaling on puberty has been very recently proposed in the female sheep (42), in which increased NKB fiber immunoreactivity, but not cell numbers, was detected in post-pubertal vs prepubertal ewes.…”

Efeito da dieta hiperlipídica sobre a responsividade de neurônios kisspeptidérgicos à leptina

“…Apesar disso, a expressão de NKB ao longo do desenvolvimento parece ser menos sensível á inibição estimulada pelo estradiol (GILL et al, 2012). O tratamento com estrógeno é capaz de diminuir a excitabilidade de neurônios Tac2-EGFP do ARC de camundongas ovariectomizadas, que pode estar relacionado com o papel dos neurônios KND em mediar a supressão da secreção pulsátil de LH induzida pelo estradiol (CHOLANIAN et al, 2014).…”

“…Além disso, há um progressivo aumento na expressão de RNAm para Tac2 e Tacr3 ao longo da maturação pós-natal, ocorrendo um pico de expressão da Tac2 no início da puberdade e uma estabilização dos níveis de expressão da Tacr3 na transição peripuberal (GILL et al, 2012;NAVARRO et al, 2012).…”

“…Essas observações realizadas em animais no início da puberdade estão de acordo com o progressivo aumento da expressão de NKB até a maturação puberal (GILL et al, 2012;GRACHEV et al, 2012;LI et al, 2014;NAVARRO et al, 2012) e o papel da DYN em restringir a maturação puberal (NAKAHARA et al, 2013). Sugerindo que a maior colocalização da NKB em relação à DYN em neurônios Kiss1-hrGFP, independente da dieta, em fêmeas no início da puberdade, pode estar envolvido com a progressão da maturação sexual.…”