Kisspeptin-10 Peptide: Research in Reproductive, Cognitive, and Energy Mechanisms

Kisspeptin-10, alternatively known as metastin, is an endogenous peptide, and a popular research compound for its potential involvement in hormone signaling processes related to puberty and reproduction.⁽¹⁾ This naturally occurring protein appears to exhibit multifaceted functionality, probably extending beyond its primary roles. 

Notably, Kisspeptin-10 appears to be involved in the modulation of mood and behavior, facilitation of angiogenesis, and regulation of renal function. Its presence within the brain has been identified, indicating  its probable capacity to suppress tumor growth and impede metastasis. However, the utmost scientific intrigue surrounding this peptide lies in its possible influence on the gonadotropin releasing hormone (GnRH) system, thereby potentially regulating reproductive function. By deciphering the intricate mechanisms underlying Kisspeptin-10’s actions, researchers aim to unravel its restorative potential in various physiological and pathological contexts. 

What is the mechanism by which Kisspeptin-10 exerts its effects?

GPR54, also known as the KISS1 receptor (KISS1R), appears to play a critical role as a GnRH receptor in certain animals, and is considered essential for the onset of puberty.⁽²⁾ The binding of Kisspeptin-10 peptide to GPR54 receptors may activate the reproductive axis by potentially inducing the release of GnRH and gonadotropin neurons. Under the influence of Kisspeptin-10, specifically within the central nervous system, it appears to stimulate over 85% of GnRH neurons, which may result in the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).⁽³⁾

Kisspeptin-10 is a peptide composed of 54 amino acids, originating from the KISS1 gene. Additionally, smaller peptide fragments such as Kisspeptin-10 13 and 14 appear to exhibit biological activity towards GPR54.⁽³⁾ These smaller peptides appear to bind to GPR54 receptors with a lower affinity but seem to be capable of triggering calcium mobilization, release of arachidonic acid, and phosphorylation of extracellular protein kinases.⁽³⁾

These events may depolarize Kisspeptin-10 neurons, which may consequently lead to the depolarization of GnRH neurons and modulation of gonadotropin release.⁽⁴⁾

How was the Kisspeptin-10 peptide discovered?

In the mid-1990s, a notable advancement was achieved when a cancer cell, upon integration with chromosome 6, appeared to induce a suppression of metastasis development and cancer cell dissemination.⁽⁵⁾ Subsequently, this specific chromosome was designated as the KISS1 gene. 

Later during the mid-2000s, several independent investigations unveiled the potential roles of Kisspeptin-10 peptide in hypogonadotropic hypogonadism, as it appears to act as a ligand for the G-protein coupled receptor 54 (GPR54).⁽⁶⁾ 

 

Research Studies on Kisspeptin-10 Peptide

Kisspeptin-10 Peptide and Gonadotropin-Releasing Hormone Release

Research suggests Gonadotropin-releasing hormone (GnRH) is synthesized and secreted by specialized GnRH neurons located in the hypothalamus. This neuropeptide appears to serve as the initial hormone released within the hypothalamic-pituitary-gonadal (HPG) axis and may exert crucial regulatory control over the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. GnRH is believed to play a pivotal role in the initiation and progression of puberty, orchestrating the maturation of gametes within the reproductive organs. The precise regulation of GnRH release and its downstream appears to prominently affect the reproductive system.

In the context of a study conducted in 2017,⁽⁷⁾ a comprehensive literature review was performed encompassing articles published between 1999 and 2016. The collective analysis of these articles indicated compelling evidence supporting the probable role of the Kisspeptin-10 system, including the KISS1 gene and its gene products, as well as GPR54 receptors, in the initiation of puberty and subsequent regulation of gonadotropin hormone release. Certain studies conducted on experimental animal models exhibiting analogous features to hypogonadotropic hypogonadism (HH) and polycystic ovarian syndrome (PCOS) reported possible aberrations within the KISS1 and GPR54 system, potentially contributing to the occurrence of reproductive disorders such as HH and PCOS.

Kisspeptide-10 Peptide and Testosterone Synthesis

Kisspeptin-10 peptide may influence the testosterone levels through a possible modulation of the circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). However, the impact of Kisspeptin-10 peptide on testosterone appears to be sex-specific. In male test models, peptide introduction appeared to cause an increase in testosterone levels, whereas in female test models, it did not appear to produce any discernible effect on testosterone. Notably, a clinical study involving six male subjects who received a derivative of Kisspeptin-10, appeared to exhibit a significant elevation in plasma testosterone levels, nearly tripling after just 90 minutes.⁽⁸⁾

Furthermore, Kisspeptin-10 peptide appears to influence the pulsatile release of LH in male test subjects, indicating its potential role in fine-tuning the normal rhythmic release of sex hormones. In another study involving healthy male subjects presented with Kisspeptin-10, a rapid and concentration-dependent elevation in serum LH levels was observed, accompanied by a concurrent increase in testosterone levels. Studies suggest that Kisspeptin-10 peptide may achieve this effect by possibly enhancing the pulsatile release of LH. At greater concentrations, Kisspeptin-10 peptide appears to induce such rapid pulsation that individual pulses become indistinguishable, resulting in continuous LH release. As stated by the researchers “Kisspeptin-10 boluses potently evoke LH secretion […], and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.”⁽⁹⁾

Kisspeptin-10 Peptide and Cognitive Improvement

Emerging data indicates that the Kisspeptin-10 peptide may have implications in the regions of the brain associated with memory consolidation and spatial orientation. Experimental studies conducted in mice suggest that the influence of these peptides may potentially ameliorate the learning and navigational impairments commonly observed in ethanol intoxication.⁽¹⁰⁾ Research also suggests that the compound may play a role in neuronal information encoding as “the ethanol-induced spatial memory impairment may also be reversed by pharmacological manipulation of the endogenous opioid system.”⁽¹⁰⁾

Kisspeptin-10 Peptide and Impact on Mood

Considering the involvement of the Kisspeptin-10 peptide in both reproductive processes and energy regulation, researchers have sought to investigate the potential influence of this peptide on emotions and behavior. To explore this relationship, a study was conducted comparing Kisspeptin-10 to a placebo in a cohort of 29 healthy male test subjects. The test models receiving Kisspeptin-10 peptide appeared to exhibit heightened activity within the limbic brain regions, which have indicated the potential peptide involvement in emotional processing. Research indicates the subjects appeared to display increased tendencies for seeking rewards, heightened drive, and overall improvement in mood.⁽¹¹⁾

These findings suggest that “kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood.”⁽¹¹⁾

Kisspeptin-10 Peptide and Energy Balance

Kisspeptin-10 neurons have long been recognized as responsive to the energy status of an individual. Perturbations in energy balance, such as both undernutrition and severe overnutrition, may attenuate the possible stimulatory effect of Kisspeptin-10 neurons on gonadotropin-releasing hormone (GnRH) release. These alterations in energy balance may lead to infertility in both male and female test models, a process in which Kisspeptin-10 may play a mediating role.

While the sensitivity of Kisspeptin-10 production and release to energy balance is widely considered concrete, emerging data suggests that Kisspeptin-10 itself may regulate energy balance. This insight stemmed from observations in genetically manipulated mice lacking the Kisspeptin-10 receptor (Kiss1r). These mice exhibited increased adiposity and reduced energy expenditure. Research indicated that the Kisspeptin-10 receptor was found to be present in adipose (fat) tissue and brown adipose tissue.⁽¹²⁾ Studies indicate a strong historical connection between the compound and energy status and reproductive fitness. It appears that the Kisspeptin-10 molecule may serve as a link that might help elucidate the neurochemical control underlying energy-modulating behaviors in the context of reproduction.

Kisspeptin-10 Peptide and Renal system

While the primary focus of Kisspeptin-10 research lies in its involvement in reproduction and the control of reproductive hormones, studies indicate that the Kisspeptin-10 peptide may hold significance in the maintenance of kidney health. Kisspeptin-10 and its receptors are distributed across various locations within the kidney and are believed to participate in signaling kidney function.  

Studies conducted in mice lacking the Kiss1 receptor indicate the possible role of the peptide in ensuring proper glomerular development during embryonic stages. However, the precise mechanism underlying this action, whether it is direct or indirect, requires further elucidation.

Research suggests of a possible link between the peptide and its potential role in regulating vascular development and the vascular response to injury. Investigations focusing on cardiovascular disease in mice suggest that the Kisspeptin-10 peptide may play some role in specific vascular beds, possibly influencing vasoconstriction and even cardiac output under certain conditions.⁽¹³⁾ The impact of the Kisspeptin-10 peptide on both kidneys and the cardiovascular system is likely associated with its effects on angiogenesis and vascular function. This characteristic may also explain its posited potential for suppressing tumor metastasis. 

Kisspeptin-10 Peptide and Food Intake

Kisspeptin-10 is considered to be widely distributed, with various brain regions, including the hippocampus, cerebellum, posterior hypothalamus, and septum, harboring this neuropeptide. Considering its presence in the nuclei responsible for regulating food intake, such as the arcuate nucleus (Arc) within the hypothalamus, the present study⁽¹⁴⁾ aimed to investigate the effects of Kisspeptin-10 on food intake.

To conduct this experiment, adult male mice aged between 6 and 8 weeks were observed and housed under standard conditions with normal temperatures. The mice were provided with a standard rodent diet and tap water throughout the study. Both overnight fasted mice and experimentally fed mice were presented with different concentrations of Kisspeptin-10 peptide or a placebo.

The results suggested that the peptide given to overnight fasted mice may have led to a concentration-dependent reduction in food intake during the initial 3-to-12-hour period. Subsequently, food intake appeared to increase during the 12-to-16-hour period, possibly resulting in overall similar food intake compared to the placebo group. These findings suggested that the Kisspeptin-10 peptide may decrease meal frequency and total meal duration while possibly increasing intervals between meals. Interestingly, meal size and eating rate appeared to remain comparable to those of the placebo-treated mice.

Kisspeptin-10 Peptide and Cancer Research

Research indicates that changes appear in the Kisspeptin-10 levels in various metastatic cancer types, including breast, bladder, gastrointestinal, prostate, pancreatic, ovarian, skin, and thyroid cancers. Ongoing research aims to possibly manipulate, modify, and comprehend the actions of Kisspeptin-10 in various cancer types. Studies suggest that the Kisspeptin-10 molecule appears to possess the potential to block metastasis and possibly reduce disease burden. Recent findings also suggest a connection between Kisspeptin-10, melatonin, and cancer, indicating their involvement in tumor suppression.

 

Synopsis

Kisspeptin-10, a neuropeptide, has been suggested to regulate reproduction and energy balance. It appears to act through the GPR54 receptor and potentially stimulates GnRH release, possibly influencing gonadotropin hormones. Studies indicate its potential role in controlling vascular development, angiogenesis, and reducing metastasis of tumors. Recent research has linked Kisspeptin levels to exposure to daylight and tumor growth rates. Further investigations are warranted to fully elucidate its underlying mechanisms and evaluate its applications.

 
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References

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