دورية أكاديمية
Dissecting the KNDy hypothesis: KNDy neuron-derived kisspeptins are dispensable for puberty but essential for preserved female fertility and gonadotropin pulsatility.
| العنوان: | Dissecting the KNDy hypothesis: KNDy neuron-derived kisspeptins are dispensable for puberty but essential for preserved female fertility and gonadotropin pulsatility. |
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| المؤلفون: | Velasco, Inmaculada, Franssen, Delphine, Daza-Dueñas, Silvia, Skrapits, Katalin, Takács, Szabolcs, Torres, Encarnación, Rodríguez-Vazquez, Elvira, Ruiz-Cruz, Miguel, León, Silvia, Kukoricza, Krisztina, Zhang, Fu-Ping, Ruohonen, Suvi, Luque-Cordoba, Diego, Priego-Capote, Feliciano, Gaytan, Francisco, Ruiz-Pino, Francisco, Hrabovszky, Erik, Poutanen, Matti, Vázquez, María J, Tena-Sempere, Manuel |
| المصدر: | Metabolism: Clinical and Experimental, 144, 155556 (2023-04-29) |
| بيانات النشر: | W.B. Saunders, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Fertility, GnRH, Gonadotropins, KNDy, Kiss1, Kisspeptins, Metabolism, Neurokinin B, Puberty, Tac2, Endocrinology, Diabetes and Metabolism, Endocrinology, Human health sciences, Endocrinology, metabolism & nutrition, Sciences de la santé humaine, Endocrinologie, métabolisme & nutrition |
| الوصف: | [en] BACKGROUND: 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.METHODS: 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.RESULTS: 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 Kiss1 in Tac2-cells led also to sex-dependent alterations in body composition, glucose homeostasis, especially in males, and locomotor activity, specifically in females.CONCLUSIONS: 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.SIGNIFICANCE STATEMENT: 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. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article peer reviewed |
| اللغة: | English |
| Relation: | https://api.elsevier.com/content/article/PII:S0026049523001592?httpAccept=text/xml; urn:issn:0026-0495; urn:issn:1532-8600 |
| DOI: | 10.1016/j.metabol.2023.155556 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/302662 |
| حقوق: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
| رقم الأكسشن: | edsorb.302662 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1016/j.metabol.2023.155556 |
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