Gonadotropin Inhibitory Hormone and Its Receptor: Potential Key to the Integration and Coordination of Metabolic Status and Reproduction

Since its discovery as a novel gonadotropin inhibitory peptide in 2000, the central and peripheral roles played by gonadotropin-inhibiting hormone (GnIH) have been significantly expanded. This is highlighted by the wide distribution of its receptor (GnIH-R) within the brain and throughout multiple peripheral organs and tissues. Furthermore, as GnIH is part of the wider RF-amide peptides family, many orthologues have been characterized across vertebrate species, and due to the promiscuity between ligands and receptors within this family, confusion over the nomenclature and function has arisen. In this review, we intend to first clarify the nomenclature, prevalence, and distribution of the GnIH-Rs, and by reviewing specific localization and ligand availability, we propose an integrative role for GnIH in the coordination of reproductive and metabolic processes. Specifically, we propose that GnIH participates in the central regulation of feed intake while modulating the impact of thyroid hormones and the stress axis to allow active reproduction to proceed depending on the availability of resources. Furthermore, beyond the central nervous system, we also propose a peripheral role for GnIH in the control of glucose and lipid metabolism at the level of the liver, pancreas, and adipose tissue. Taken together, evidence from the literature strongly suggests that, in fact, the inhibitory effect of GnIH on the reproductive axis is based on the integration of environmental cues and internal metabolic status.

The Role of GnIH in Biological Rhythms and Social Behaviors

Gonadotropin-inhibitory hormone (GnIH) was first discovered in the Japanese quail, and peptides with a C-terminal LPXRFamide sequence, the signature protein structure defining GnIH orthologs, are well conserved across vertebrate species, including fish, reptiles, amphibians, avians, and mammals. In the mammalian brain, three RFamide-related proteins (RFRP-1, RFRP-2, RFRP-3 = GnIH) have been identified as orthologs to the avian GnIH. GnIH is found primarily in the hypothalamus of all vertebrate species, while its receptors are distributed throughout the brain including the hypothalamus and the pituitary. The primary role of GnIH as an inhibitor of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin release is well conserved in mammalian and non-mammalian species. Circadian rhythmicity of GnIH, regulated by light and seasons, can influence reproductive activity, mating behavior, aggressive behavior, and feeding behavior. There is a potential link between circadian rhythms of GnIH, anxiety-like behavior, sleep, stress, and infertility. Therefore, in this review, we highlight the functions of GnIH in biological rhythms, social behaviors, and reproductive and non-reproductive activities across a variety of mammalian and non-mammalian vertebrate species.

Effects of LPXRFamide peptides on chub mackerel gonadotropin secretion

Gonadotropin-inhibitory hormone (GnIH), a neuropeptide, suppresses gonadotropin (GTH) secretion in birds and mammals. In fish, the GnIH homolog LPXRFamide (LPXRFa) produces mature peptides with species-dependent effects on sexual reproduction. Here, we investigated the effects of LPXRFa on GTH secretion in the chub mackerel (cm; Scomber japonicus). We cloned cmlpxrfa (603 bp) and cmlpxrfa-r (1,416 bp). Additionally, we isolated lpxrfa from the bluefin tuna (Thunnus orientalis) to confirm the conservation of the LPXRFa mature sequence. Phylogenetic analysis showed that the LPXRFa precursor protein produces three mature peptides, LPXRFa-1, −2, and − 3, in both species. Reverse transcription-quantitative PCR revealed that cmlpxrfa is expressed in the hypothalamus and thalamus and midbrain (T.MB), and sexual differences were observed. Receptor expression was observed in the pre-optic area, hypothalamus, T.MB, and pituitary. Female hypothalamic lpxrfa expression did not change during puberty. Reporter gene assay showed that LPXRFa induced receptor activation via the CRE and SRE signaling pathways. However, in the presence of forskolin, an intracellular cyclic AMP enhancer, none of the LPXRFa could suppress receptor activity. The in vitro bioassay results showed that gonadotropin-releasing hormone-1 (GnRH1) had no effect on follicle-stimulating hormone (FSH) secretion, whereas the three LPXRFa significantly increased FSH secretion in pituitary cells from male chub mackerel. Contrarily, GnRH1 and three LPXRFa significantly increased luteinizing hormone (LH) secretion. The in vivo administration of LPXRFa had no effect on fshb and lhb expression in pre-pubertal and mature male chub mackerel. Overall, cmLPXRFa lacks the ability to suppress GTH secretion but can promote GTH secretion.