Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide
Abstract
The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.
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In gonadectomized rats, gonad removal increased KiSS1 mRNA levels, and gonadal steroid replacement reversed this increase.
“The first observations indicating that kisspeptin neurons might be involved in the negative feedback regulation by gonadal steroids were seen in gonadectomized rats, where removal of the gonads significantly increased KiSS 1 mRNA levels, and this effect was reversed by replacement with gonadal steroids (Navarro et al., 2004).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Navarro et al., 2004
Cites
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“In this context, the demonstration that inactivating mutations of their putative receptor led to reproductive failure due to hypogonadotropic hypogonadism highlighted a previously unsuspected role for the KiSS-1/ GPR54 system in the control of the gonadotropic axis (8, 9).”
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“…that kisspeptin neurons might be involved in the negative feedback regulation by gonadal steroids were seen in gonadectomized rats, where removal of the gonads significantly increased KiSS 1 mRNA levels, and this effect was reversed by replacement with gonadal steroids (Navarro et al., 2004).”
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- Authors
- Navarro, V. M., Castellano, J. M., Fernández-Fernández, R., Barreiro, M. L., Roa, J., Sanchez-Criado, J. E., Aguilar, E., Dieguez, C., Pinilla, L., & Tena-Sempere, M.
- Affiliations
- University of Córdoba (ES)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-10-01
- Volume
- 145
- Issue
- 10
- Pages
- 4565-4574
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2121986949
- Cited by
- 711
- References
- 6
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 17 · 2021: 24 · 2020: 24 · 2019: 30 · 2018: 30 · 2017: 35 · 2016: 36 · 2015: 27 · 2014: 38 · 2013: 51 · 2012: 48
- FWCI
- 35.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- KISS1, GPR54, kisspeptin, hypothalamus, luteinizing hormone secretion, puberty, gonadotropic axis, postnatal development, estrous cycle, gonadectomy, hypothalamic gene expression, hypogonadotropic hypogonadism
- MeSH terms
- Receptors, Kisspeptin-1, Aging, Animals, Animals, Newborn, Castration, Estradiol, Estrus, Female, Hormones, Hypothalamus, Injections, Intraventricular, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Male, Peptide Fragments, Proteins, RNA, Messenger, Rats, Wistar, Receptors, Neuropeptide, Gene Expression Regulation, Developmental, Receptors, G-Protein-Coupled, Mice, Rats, Kisspeptins
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