Endocrine Abstracts

Kiss1 neurons are essential elements in the central pathways controlling the reproductive axis. In rodents, two major hypothalamic populations of Kiss1 neurons exist, in the arcuate nucleus (ARC) and in the rostral periventricular area of the third ventricle (RP3V). The majority of ARC Kiss1 neurons express two others neuropeptides, neurokinin B (NKB; encoded by Tac2) and dynorphin (Dyn); hence, this population has been named KNDy. Yet, NKB-only and Kiss1-only neurons are also found in the ARC, but the relative contribution of the different subsets of Kiss1 populations to the control of reproductive function, and its modulation by metabolic factors, remains unexplored. To define the precise roles of KNDy-born kisspeptin, and hence of KNDy (vs. Kiss1-only) neurons, we report herein the generation and initial characterization of the first mouse line, named TaK-KO, with conditional ablation of Kiss1 in Tac2 expressing-neurons, produced by crossing the JAX Tac2-Cre mouse with our novel Kiss1 loxP mouse. Male and female TaK-KO mice displayed a significant decrease of ARC Kiss1 mRNA expression at 2-months of age, while Tac2 (NKB) mRNA levels remained unaltered. Despite this drop of ARC Kiss1 expression, puberty onset (evidenced by vaginal opening and first estrus in females, and preputial separation in males) occurred at normal timing. Further, the absence of Kiss1 in KNDy neurons did not significantly affect basal LH levels, neither did it alter LH responses to Senktide (NKB agonist) or kisspeptin-10. Yet, uterus weights were markedly decreased in 2-mo-old TaK-KO females, suggesting an incipient perturbation of the reproductive axis. This contention is further supported by initial analyses in 6-mo-old TaK-KO female mice, which displayed overt irregularities in estrous cyclicity; characterization of LH pulsatility and ovarian morphology is in progress. In parallel, our initial metabolic analyses suggest that the ablation of Kiss1 in KNDy neurons leads also to significant changes in body composition (increase of fat mass), detectable in 4 mo-old males and females, together with modest changes of glucose and insulin tolerance, mainly noticed in males. In sum, we report herein the first mouse line with conditional ablation of Kiss1 in KNDy neurons. Our data suggest that KNDy-born kisspeptins are dispensable for puberty onset but required for proper maintenance of reproductive and metabolic homeostasis in adulthood. Ongoing studies, using different metabolic and reproductive challenges, are currently in progress in this novel mouse line to tease apart the specific roles of KNDy-derived kisspeptins in the control of these key bodily functions.