Discovery Of Gonadotropin-inhibitory Hormone Research Articles

Peripheral 5-HT Mediates Gonadotropin-Inhibitory Hormone-Induced Feeding Behavior and Energy Metabolism Disorder in Chickens via the 5-HT2C Receptor

Introduction: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. Methods: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. Results: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. Discussion: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders.

Gonadotropin inhibitory hormone receptors (GnIHRs): Molecular characterization and synergistic effect of different drugs in Indian major carp, Labeo catla

After the discovery of Gonadotropin-inhibitory hormone (GnIH) in birds in 2000, it showed different roles in different vertebrate classes and even in different species of same classes. In birds and mammals, GnIH inhibits the expression of gonadotropins during reproduction, while in fishes it exerts both inhibitory and stimulatory effect on reproduction. The current study evaluates the role of GnIH during reproduction in Labeo catla. The partial cDNA sequence of GnIHR1 and GnIHR3 receptor genes was identified by degenerate PCR. The mRNA expression analysis of GnIHRs during different reproductive phases showed that the expression of all three GnIH receptor genes is highest during spawning phase. The expression of GnIH receptors is detected in both brain and gonads except for GnIHR3 which only expressed in gonads. The in vivo experiments with GnIH antagonist, RF313 drastically reduced the expression level of reproduction related genes like LH, FSH, and GnRH at 1 h post-injection. In another experiment the surge induced by cGnIH-III peptide on gonadotropins gene expression is further increased when co-injected with LHRHa. However, co-injection of melatonin along with cGnIH-III peptide had opposite effects. These results showed that the GnIH/GnIHRs system has positive effect on reproduction in L. catla.

How to Contribute to the Progress of Neuroendocrinology: Discovery of GnIH and Progress of GnIH Research.

It is essential to discover novel neuropeptides that regulate the functions of pituitary, brain and peripheral secretory glands for the progress of neuroendocrinology. Gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide stimulating gonadotropin release was isolated and its structure was determined by Schally's and Guillemin's groups at the beginning of the 1970s. It was subsequently shown that GnRH is highly conserved among vertebrates. GnRH was assumed the sole hypothalamic neuropeptide that regulates gonadotropin release in vertebrates based on extensive studies of GnRH over the following three decades. However, in 2000, Tsutsui's group isolated and determined the structure of a novel hypothalamic neuropeptide, which inhibits gonadotropin release, in quail, an avian species, and named it gonadotropin-inhibitory hormone (GnIH). Following studies by Tsutsui's group demonstrated that GnIH is highly conserved among vertebrates, from humans to agnathans, and acts as a key neuropeptide inhibiting reproduction. Intensive research on GnIH demonstrated that GnIH inhibits gonadotropin synthesis and release by acting on gonadotropes and GnRH neurons via GPR147 in birds and mammals. Fish GnIH also regulates gonadotropin release according to its reproductive condition, indicating the conserved role of GnIH in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in vertebrates. Therefore, we can now say that GnRH is not the only hypothalamic neuropeptide controlling vertebrate reproduction. In addition, recent studies by Tsutsui's group demonstrated that GnIH acts in the brain to regulate behaviors, including reproductive behavior. The 18 years of GnIH research with leading laboratories in the world have significantly advanced our knowledge of the neuroendocrine control mechanism of reproductive physiology and behavior as well as interactions of the HPG, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. This review describes how GnIH was discovered and GnIH research progressed in this new research era of reproductive neuroendocrinology.

Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty

It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction.

Control of the reproductive axis: Balancing act between stimulatory and inhibitory input

As for most vertebrates, reproduction in poultry is controlled by an integrated axis [the hypothalamo-pituitary-gonadal (HPG) axis]. External and internal cues are integrated at the level of the hypothalamus to initiate gonadal recruitment and control the subsequent reproductive cycle. Until recently, it was believed that the HPG was exclusively under stimulatory control from hypothalamic gonadotropin releasing hormone (GnRH). However in 2000, the discovery of gonadotropin inhibitory hormone (GnIH), an inhibitory peptide, changed this dogma. Since then, evidence accumulated to confirm that in fact the HPG is under a dual control system with a stimulatory and an inhibitory branch. In this paper, we review the organization of this dual control system, the mechanisms controlling the synthesis and release of GnRH and GnIH, and the possible integration and interactions between the two branches to regulate pituitary gonadotropes’ function. Furthermore, as light perception and photoperiod are the primary cues utilized by the poultry industry in controlled environments, special consideration was given to potential practical applications.

Review: evolution of GnIH and related peptides structure and function in the chordates.

Discovery of gonadotropin-inhibitory hormone (GnIH) in the Japanese quail in 2000 was the first to demonstrate the existence of a hypothalamic neuropeptide inhibiting gonadotropin release. We now know that GnIH regulates reproduction by inhibiting gonadotropin synthesis and release via action on the gonadotropin-releasing hormone (GnRH) system and the gonadotrope in various vertebrates. GnIH peptides identified in birds and mammals have a common LPXRF-amide (X = L or Q) motif at the C-terminus and inhibit pituitary gonadotropin secretion. However, the function and structure of GnIH peptides are diverse in fish. Goldfish GnIHs possessing a C-terminal LPXRF-amide motif have both stimulatory and inhibitory effects on gonadotropin synthesis or release. The C-terminal sequence of grass puffer and medaka GnIHs are MPQRF-amide. To investigate the evolutionary origin of GnIH and its ancestral structure and function, we searched for GnIH in agnathans, the most ancient lineage of vertebrates. We identified GnIH precursor gene and mature GnIH peptides with C-terminal QPQRF-amide or RPQRF-amide from the brain of sea lamprey. Lamprey GnIH fibers were in close proximity to GnRH-III neurons. Further, one of lamprey GnIHs stimulated the expression of lamprey GnRH-III peptide in the hypothalamus and gonadotropic hormone β mRNA expression in the pituitary. We further identified the ancestral form of GnIH, which had a C-terminal RPQRF-amide, and its receptors in amphioxus, the most basal chordate species. The amphioxus GnIH inhibited cAMP signaling in vitro. In sum, the original forms of GnIH may date back to the time of the emergence of early chordates. GnIH peptides may have had various C-terminal structures slightly different from LPXRF-amide in basal chordates, which had stimulatory and/or inhibitory functions on reproduction. The C-terminal LPXRF-amide structure and its inhibitory function on reproduction may be selected in later-evolved vertebrates, such as birds and mammals.

Phylogenetic aspects of gonadotropin‐inhibitory hormone and its homologs in vertebrates

The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion in vertebrates, but a hypothalamic neuropeptide inhibiting gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, we discovered a novel hypothalamic dodecapeptide that inhibits gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). GnIH acts on the pituitary and GnRH neurons in the hypothalamus via a novel G protein-coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. The pineal hormone melatonin is a key factor controlling GnIH neural function. Because GnIH exists and functions in several avian species, GnIH is considered to be a new key neuropeptide controlling avian reproduction. After the discovery of GnIH in birds, the presence of GnIH homologs has been demonstrated in other vertebrates from fish to humans. Interestingly, mammalian GnIH homologs also act to inhibit reproduction by decreasing gonadotropin release in several mammalian species. It is concluded that GnIH and GnIH homologs act to inhibit gonadotropin release in higher vertebrates.

Gonadotropin-inhibitory hormone in seasonally-breeding songbirds: neuroanatomy and functional biology

The discovery of gonadotropin-inhibitory hormone (GnIH) in Japanese Quail Coturnix japonica has given us a new perspective on the neuroendocrine control of reproductive physiology and behavior. Using highly photoperiodic passerine songbirds as our model system, we have been able to investigate GnIH neuroanatomy and functional biology. The distribution of GnIH peptide is similar among the galliform and passerine species studied so far. We have identified GnIH cDNA and localized its transcript in Gambel’s White-crowned Sparrow Zonotrichia leucophrys gambelii. There is a high degree of homology between the galliform and passerine GnIH cDNA sequences and peptides. Based on transcript localization, GnIH precursor polypeptide is only produced in the paraventricular nucleus, yet GnIH-immunoreactive fibers project to multiple brain areas, suggesting multiple physiological and behavioral functions. GnIH immunoreactive neurons appear to contact gonadotropin-releasing hormone (GnRH)-I and -II neurons, raising the possibility of direct regulation of GnRH by GnIH. In a photoperiod experiment, GnIH neurons increased in area during the termination of reproduction in Song Sparrows, Melospiza melodia, implying temporal photoperiodic regulation of this neuropeptide. Using peripheral administration of GnIH in vivo, we demonstrated rapid inhibition of LH release in laboratory and field experiments. Furthermore, we sought to determine the effects of central infusions of GnIH. Centrally-administered GnIH rapidly reduced circulating LH and significantly reduced the number of copulation solicitations performed in response to song playback, with no reduction of locomotor activity. Central infusion of rhodaminated GnIH elucidated putative GnIH binding sites in the median eminence close to GnRH-I fiber terminals, and in the midbrain on or close to GnRH-II neurons. These data demonstrate direct effects of GnIH upon reproductive physiology and behavior, possibly at multiple physiological levels and over different time-frames. Thus, the discovery of GnIH has unearthed a complex and interesting system for the regulation of avian reproductive biology.

Discovery of gonadotropin-inhibitory hormone in a domesticated bird, its mode of action and functional significance

Neuropeptide control of gonadotropin secretion at the level of the anterior pituitary gland is primarily through the stimulatory action of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH) in vertebrates. Until recently, no neuropeptide that directly inhibits gonadotropin secretion had been identified. In 2000, we discovered a novel hypothalamic dodecapeptide that directly inhibits gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). A gonadotropin inhibitory system is an intriguing concept and provides us with an unprecedented opportunity to study the regulation of avian reproduction from an entirely novel standpoint. To elucidate the mode of action of GnIH, we then identified a novel G protein-coupled receptor for GnIH in quail. The receptor possessed seven transmembrane domains and specifically bound to GnIH in a concentration-dependent manner. The GnIH receptor was found to be expressed in the pituitary and several brain regions including the hypothalamus. These results indicate that GnIH acts directly on the pituitary via GnIH receptor to inhibit gonadotropin release. GnIH may also act on the hypothalamus to inhibit GnRH release, because GnIH fibers were observed to contact GnRH cell bodies. To demonstrate the functional significance of GnIH and its potential role as a key neuropeptide involved in avian reproduction, we further investigated the action of GnIH on gonadal development and maintenance in quail. Chronic treatment with GnIH inhibited photoinduced testicular development and maintenance by decreasing gonadotropin synthesis and release. Melatonin is a key factor involved in GnIH neural function. Quail GnIH neurons were found to contain melatonin receptor and melatonin stimulated expression of GnIH mRNA and mature GnIH peptide in a dose-dependent manner. It is concluded that GnIH is capable of transducing photoperiodic information via changes in the melatonin signal and of influencing the reproductive axes of birds.