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Kisspeptin: What is it and what is its function?

The discovery of kisspeptin as a critical central factor in regulating the release of GnRH (gonadotropin-releasing hormone) was of great importance for understanding neuroendocrine regulation in human reproduction. It activates the signaling pathway by binding to its receptor, the kisspeptin receptor (KISS1R), promoting the secretion of GnRH and thus regulating the hypothalamic-pituitary-gonad (HPG) axis.

Recent studies have revealed that kisspeptin neurons located in the arcuate nucleus (ARC) coexpress neurokinin B (NKB) and dynorphin (Dyn), forming the so-called KNDy neurons. These neurons play a crucial role in estrogen's positive and negative feedback on GnRH secretion. Furthermore, initiating puberty and regulating processes such as follicular development, oocyte maturation, and ovulation in the female reproductive system through the HPG axis is essential.



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What is Kisspeptin? 

Kisspeptin is a neuropeptide discovered in 1996. Interestingly, it was later revealed to be associated initially with cancer metastasis but is a crucial regulator of reproduction. It activates the kisspeptin receptor, which triggers events that influence the reproductive system.

The KISS1 gene was first found by Lee and colleagues while studying different metastatic abilities of human melanoma cells. Therefore, the gene's name was inspired by the place of its discovery, where Hershey’s chocolate called “kisses” was produced.

Kisspeptin acts through the G protein-coupled receptor, GPR54, and is a fundamental part of regulating the HPG axis. Its action occurs before GnRH, controlling the secretion of LH L.H.d FSH. In addition to its role in the hypothalamus, it also directly affects the gonads, acting in an autocrine-paracrine manner. In women, kisspeptin negatively regulates preantral follicular development and increases oocyte maturity. Kisspeptin is associated with spermatogenesis in men, although its detailed role is not entirely understood. 


Function of kisspeptin in Regulating reproduction

The primary function of kisspeptin is regulating the hypothalamic-pituitary-gonad (HPG) axis, a complex hormonal control system associated with reproduction. Kisspeptin acts as a true conductor in this process. In particular, it plays a central role in gonadotropin-releasing hormone (GnRH) secretion. This essential hormone triggers the release of sex hormones such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are necessary for the functioning of male and female reproductive organs. One of the most exciting findings is that kisspeptin controls puberty. It signals when the time is suitable for the body to enter the reproductive phase, initiating sexual development.

In addition, kisspeptin also plays a vital role in female reproduction, influencing the development of ovarian follicles, egg maturation, and ovulation. In male reproduction, kisspeptin regulates the function of Leydig cells, which are involved in the production of testosterone, and affects spermatogenesis and sperm function. Additionally, it plays a role in reproductive behaviors such as mounting, thrusting, and ejaculation.


Challenges and Perspectives of Kisspeptin

In recent years, significant advances in mammalian research have improved our understanding of the mechanisms related to kisspeptin. Modern approaches, such as optogenetics, mathematical models, and in vivo calcium imaging, have contributed to answering long-standing questions about negative and positive feedback and the role of the kisspeptin/KISS1R system in female reproduction. There are still open questions, especially about male reproduction, where the function of kisspeptin in steroidogenesis, sperm function, and reproductive behaviors requires further investigation.

Despite advances, many studies have only been conducted in animal models, requiring more robust evidence to apply findings to human reproduction. Furthermore, the small populations of kisspeptin neurons found in the brain's limbic system present additional challenges, as their function and lineage need to be explored. Developing new technologies promises to bring new insights to this constantly evolving area.


Clinical practice 

Understanding the role of kisspeptin in regulating the reproductive system has proven to be of great relevance. It can be a tool for the diagnosis and treatment of disorders related to reproduction, such as precocious puberty, hypogonadism, and infertility. Furthermore, continued research in this field can improve therapeutic options, allowing for more personalized and practical approaches. Kisspeptin is establishing itself as a crucial component in the field of reproductive medicine, bringing new perspectives to those facing reproductive challenges.


References

Watch the video on Science Play with Omar de Faria: Circadian cycle and fertility: What is the relation?  

XIE, Qinying; KANG, Yafei; ZHANG, Chenlu; Xie, Ye; WANG, Chuxiong; LIU, Jiang; YU, Caiqian; ZHAO, Hu; HUANG, Donghui. The Role of Kisspeptin in the Control of the Hypothalamic-Pituitary-Gonadal Axis and Reproduction. Frontiers In Endocrinology, [S.LS.L.v. 13, p. 1, 28 June. 2022. Frontiers Media SA.S.A

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