Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism

Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). AVPV kisspeptin is thought to regulate the estrogen-induced positive feedback control of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), and the preovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely coexpress neurokinin B and dynorphin A (collectively named KNDy neurons), are thought to mediate estrogen-induced negative feedback control of GnRH/LH and be the major regulators of pulsatile GnRH/LH release. However, definitive data to delineate the specific roles of AVPV versus ARC kisspeptin neurons in the control of GnRH/LH release is lacking. Therefore, we generated a novel mouse model targeting deletion of Kiss1 to the ARC nucleus (Pdyn-Cre/Kiss1^fl/fl KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knockout was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1^fl/fl KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared with controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1^fl/fl KO males also exhibited disrupted LH pulsatility, hypogonadism, and variable, defective spermatogenesis, and subfertility. The timing of pubertal onset in males and females was equivalent to controls. These findings add to the current body of evidence for the critical role of kisspeptin in ARC KNDy neurons in GnRH/LH pulsatility in both sexes, while directly establishing ARC kisspeptin's role in regulating estrous cyclicity in female mice, and gametogenesis in both sexes, and culminating in disrupted fertility. The Pdyn-Cre/Kiss1^fl/fl KO mice present a novel mammalian model of postpubertal central hypogonadism.NEW & NOTEWORTHY We demonstrate through a novel, conditional knockout mouse model of arcuate nucleus (ARC)-specific kisspeptin in the KNDy neuron that ARC kisspeptin is critical for estrous cyclicity in female mice and GnRH/LH pulsatility in both sexes. Our study reveals that ARC kisspeptin is essential for normal gametogenesis, and the loss of ARC kisspeptin results in significant hypogonadism, impacting fertility status. Our findings further confirm that normal puberty occurs despite a loss of ARC kisspeptin.