β‐Klotho sustains postnatal GnRH biology and spins the thread of puberty

Hypogonadotropic hypogonadism is a syndrome found to be isolated (IHH) or associated with anosmia, corresponding to the Kallmann syndrome (KS). It comprises a defect in gonadotropin‐releasing hormone (GnRH) secretion and absent or delayed puberty. Genetic causes have been identified with a high genetic heterogeneity. Fibroblast growth factor receptor 1 (FGFR1), a tyrosine kinase receptor, was one of the first genes whose mutations were identified as causative in KS. FGFR1 is responsible for the formation of the GnRH neuron system. Studying patients has not only allowed the identification of new etiologies for this syndrome but also helped to unravel the signaling pathways involved in the development of GnRH neurons and in GnRH control and function. The FGF21/FGFR1/Klotho B (KLB) signaling pathway mediates the response to starvation and other metabolic stresses. Preventing reproduction during nutritional deprivation is an adaptive process that is essential for the survival of species. In this work, Xu et al (2017), using a candidate gene approach, provide a description of the essential role played by this pathway in GnRH biology and in the pathogenesis of IHH and KS. They establish a novel link between metabolism and reproduction in humans.