Abstract: Kiss1 neurons in the hypothalamic arcuate-nucleus (ARC) play key roles in the control of GnRH pulsatility and fertility. A fraction of ARC Kiss1 neurons, termed KNDy, co-express neurokinin B (NKB; encoded by Tac2). Yet, NKB- and Kiss1-only neurons are also found in the ARC, while a second major Kiss1-neuronal population is present in the rostral hypothalamus. The specific contribution of different Kiss1 neuron sub-sets and kisspeptins originating from them to the control of reproduction and eventually other bodily functions remains to be fully determined. To tease apart the physiological roles of KNDy-born kisspeptins, conditional ablation of Kiss1 in Tac2 -expressing cells was implemented in vivo. To this end, mice with Tac2 cell-specific Kiss1 KO (TaKKO) were generated and subjected to extensive reproductive and metabolic characterization. TaKKO mice displayed reduced ARC kisspeptin content and Kiss1 expression, with greater suppression in females, which was detectable at infantile-pubertal age. In contrast, Tac2 /NKB levels were fully preserved. Despite the drop of ARC Kiss1 /kisspeptin, pubertal timing was normal in TaKKO mice of both sexes. However, young-adult TaKKO females displayed disturbed LH pulsatility and sex steroid levels, with suppressed basal LH and pre-ovulatory LH surges, early-onset subfertility and premature ovarian insufficiency. Conversely, testicular histology and fertility were grossly conserved in TaKKO males. Ablation of Kiss 1 in Tac2 -cells led also to sex-dependent alterations in body composition, glucose homeostasis, especially in males, and locomotor activity, specifically in females. Our data document that KNDy-born kisspeptins are dispensable/compensable for puberty in both sexes, but required for maintenance of female gonadotropin pulsatility and fertility, as well as for adult metabolic homeostasis. Neurons in the hypothalamic arcuate nucleus (ARC) co-expressing kisspeptins and NKB, named KNDy, have been recently suggested to play a key role in pulsatile secretion of gonadotropins, and hence reproduction. However, the relative contribution of this Kiss1 neuronal-subset, vs. ARC Kiss1-only and NKB-only neurons, as well as other Kiss1 neuronal populations, has not been assessed in physiological settings. We report here findings in a novel mouse-model with elimination of KNDy-born kisspeptins, without altering other kisspeptin compartments. Our data highlights the heterogeneity of ARC Kiss1 populations and document that, while dispensable/compensable for puberty, KNDy-born kisspeptins are required for proper gonadotropin pulsatility and fertility, specifically in females, and adult metabolic homeostasis. Characterization of this functional diversity is especially relevant, considering the potential of kisspeptin-based therapies for management of human reproductive disorders. Tac2 -specific Kiss1 knock-out (TaKKO) mice were generated using a Cre-loxP approach, as a mean to ablate kisspeptin production in KNDy neurons (which also express Tac2, encoding NKB), while preserving kisspeptin output from Kiss1-only cells (left). Sex-biased impact of TaKKO resulted in a drastic reduction of Kiss1 expression in the arcuate nucleus and overt reproductive (and metabolic) phenotypes in females, while in males, suppression of hypothalamic Kiss1 expression was milder, without major reproductive (or metabolic) alterations. Main phenotypic features are summarized in the boxes (right). [Display omitted] • Kiss1 neurons in the ARC are heterogeneous, with a large subset co-expressing NKB and Dyn (KNDy) • A mouse line with Tac2-specific ablation of Kiss1 allows assessing the roles of KNDy-born kisspeptins • KNDy-born kisspeptins are dispensable/compensable for puberty onset in both sexes • KNDy-born kisspeptins are required for maintenance of female gonadotropin pulsatility and fertility • KNDy-born kisspeptins modulate also adult metabolic homeostasis [ABSTRACT FROM AUTHOR]
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