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

Abstract

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.

Figure 1. Binding of paracrine FGF8 and endocrine FGF21 to FGFR1c

The binding of paracrine FGF8 to FGFR1c involves the conserved hydrophobic groove in the immunoglobulin III domain (D3) of FGFR1c including L342 (L). The binding of endocrine FGFs necessitates an absolute coreceptor, KLB for which binding to FGFR1c also involves the hydrophobic groove of D3 and L342. There is thus a competitive binding with FGF8.

Figure 2. Consequences of paracrine or endocrine FGF deficiencies during embryonic and postnatal life on the neuroendocrine control of reproduction

During the embryonic development, the paracrine FGF8 binds FGFR1c. Deficient FGF8 signaling results in absence of GnRH neuron development in the hypothalamus. During postnatal life, the endocrine FGF21, secreted under the influence of metabolic stimuli, acts on the liver and adipose tissue (WAT, white adipose tissue; BAT, brown adipose tissue) and reaches the hypothalamus through fenestrated capillaries (FC) of the median eminence (ME) or of the organum vasculosum of the lamina terminalis. FGF21 binds FGFR1c and the obligate coreceptor KLB. Deficient KLB is associated with normal embryonic GnRH neuron development but with a block in GnRH secretion during postnatal development. There is an altered secretion of LH and FSH by the pituitary (P) leading to altered puberty and fertility.