Differential hypothalamic regulation of FSH and LH secretion from the fish pituitary by GnRH and CCK.

In brief: The hypothalamus-pituitary-gonad axis integrates environmental and internal signals to tune reproductive functions. We hypothesized that in fish, Gnrh predominantly stimulates luteinizing hormone (LH) secretion, while Cck selectively regulates follicle-stimulating hormone (FSH), thereby uncovering a novel role for Cck as a metabolic gatekeeper that links reproductive activity with nutritional status. Abstract: In fish, the hypothalamus-pituitary-gonad axis governs reproduction in response to environmental and internal signals. FSH regulates gonadal growth, while LH controls maturation. Gonadotropin-releasing hormone (Gnrh) plays a key role in this process, while the role of the satiety hormone cholecystokinin (Cck) is under investigation. We hypothesized that Gnrh and Cck differentially regulate tilapia LH and FSH, reflecting distinct reproductive and metabolic roles. Gnrh receptor (r) 1 was localized to FSH cells and detected only in juvenile fish, while GnRrhr3 was found in LH cells across both juvenile and mature stages. GnRH stimulation significantly increased LH release, while FSH levels showed only a moderate rise. Structural analysis revealed that Gnrhr3 exhibits more stable and rapid ligand binding and activates protein kinase A and protein kinase C (PKC) pathways, whereas Gnrhr1 signals exclusively through the PKC/Ca2+ pathway. Elevated FSH levels and gnrhr 1 expression were observed during early vitellogenesis, coinciding with increased cck-rba expression in FSH cells. Cck-positive neurons originating in the brain were observed to terminate in the adenohypophysis, specifically near FSH-secreting cells. In addition, c ck-rba was exclusively expressed in FSH cells, and tilapia Cck injection significantly elevated plasma FSH levels while reducing food intake, highlighting the role of Cck in linking reproduction to nutritional status. Together, these findings indicate that Gnrh predominantly regulates LH secretion via Gnrhr3, while Cck, through Cck-rba, specifically controls FSH, linking reproduction to nutritional status. Cck acts as a metabolic gatekeeper, aligning gonadal development with energy availability and ensuring reproduction when energy is sufficient.