Kisspeptin-10 Peptide

Kisspeptin-10 is a naturally occurring peptide derived from the KISS1 gene.(2) The KISS1 gene encodes a larger precursor polypeptide of approximately 145 amino acids, which is enzymatically cleaved into shorter peptide fragments. One of these fragments is a 54-amino-acid peptide, which is further processed into Kisspeptin 45–54, commonly referred to as Kisspeptin-10.(6)

The KISS1 gene has been widely studied for its role as a metastasis suppressor, particularly in melanomas and breast carcinomas, where it is thought to inhibit abnormal cell growth and the spread of cancerous cells.(2) Although initially characterised for this function, subsequent research has suggested that Kisspeptin-10 may also have important roles within the endocrine system, particularly through its activity in the hypothalamus and pituitary gland, where it may influence reproductive processes.(3)

Studies conducted in the mid-2000s proposed that Kisspeptin-10 may be involved in the regulation of hypogonadotropic hypogonadism, as it acts as a ligand for the G-protein coupled receptor GPR54 (also known as KISS1R).(5) Hypogonadism is a condition characterised by reduced or absent production of sex hormones, and in the case of hypogonadotropic hypogonadism, this dysfunction arises from impaired signalling within the hypothalamus or pituitary gland.(1) Gonadotropin-releasing hormone (GnRH) plays a central role in this process by stimulating the pituitary to release follicle-stimulating hormone (FSH) and luteinising hormone (LH), both of which are essential for normal reproductive function. A deficiency in GnRH, FSH, or LH is considered a key contributing factor in the development of hypogonadotropic hypogonadism.

Overview

GPR54, also known as the KISS1 receptor (KISS1R),(7) has been proposed by researchers to play a key role in the regulation of gonadotropin-releasing hormone (GnRH).(1) It is suggested that Kisspeptin-10 may exert its effects by binding to GPR54 receptors, thereby activating the reproductive axis through stimulation of GnRH release and subsequent activation of gonadotropin-secreting neurons.(7)

Kisspeptin peptides are derived from the KISS1 gene, which encodes a larger precursor that is cleaved into biologically active fragments. Among these, smaller peptides such as Kisspeptin-10, Kisspeptin-13, and Kisspeptin-14 have been identified and are thought to retain activity at GPR54 receptors.(7) These fragments are proposed to bind with relatively low affinity but may still initiate intracellular signalling events, including calcium mobilisation, arachidonic acid release, and phosphorylation of extracellular signal-regulated kinases. Such signalling activity may lead to depolarisation of Kisspeptin-responsive neurons and, in turn, influence GnRH neuron activation and gonadotropin release.(9)

Research into Kisspeptin-10 has explored its potential involvement across a range of physiological functions, and multiple hypotheses have been proposed regarding its mechanisms of action, including those outlined below:(8)

  • That the Kisspeptin-10 peptide may potentially stimulate GnRH release;

  • The peptide may potentially stimulate endogenous gonadotropin release in less-fertile animal models;

  • Peptide concentrations may possibly induce desensitization and suppression of the hypothalamus, pituitary gland, and gonadal axis.

Chemical Makeup

  • Molecular Formula: C63H83N17O14

  • Molecular Weight: 1302.4 g/mol

  • Other Known Titles: Kisspeptin 45-54

Research and Clinical Studies
Kisspeptin-10 and Reproduction

As part of a 2017 study,(10) a comprehensive literature review was conducted, analysing research published between 1999 and 2016. Based on the collective findings, researchers suggested that experimental evidence may support the hypothesis that the Kisspeptin-10 system—including the KISS1 gene, its peptide products, and the GPR54 receptors—could play a role in regulating the release of gonadotropin hormones.

In addition, several experimental studies using animal models with features resembling hypogonadotropic hypogonadism (HH) and polycystic ovarian syndrome (PCOS) indicated that disruptions within the KISS1–GPR54 system may contribute to the development of these reproductive disorders. Overall, the review concluded that Kisspeptin-10 may function as a neuropeptide regulator of GnRH release, highlighting its potential importance within the reproductive endocrine axis.

Kisspeptin-10 and Delayed Hormonal Development

The primary objective of this study(13) was to assess the potential effects of Kisspeptin-10 in research models exhibiting stunted developmental characteristics. Researchers proposed that the peptide might stimulate gonadal hormone release and help regulate reproductive function in these models. To investigate this, subjects were randomly administered either Kisspeptin-10 or gonadotropin-releasing hormone (GnRH), and luteinising hormone (LH) levels were monitored overnight.

Following this initial phase, all models were exposed to GnRH for six consecutive days, after which LH levels were reassessed. The results indicated that approximately 47% of the experimental group demonstrated a positive response associated with Kisspeptin-10 exposure, reflected by increased LH levels. A further 6% exhibited a moderate or intermediate response, while the remaining 47% showed no measurable response to the peptide. These findings suggest variability in responsiveness, with a subset of models potentially benefiting from Kisspeptin-10 in terms of LH stimulation.

Kisspeptin-10 and Emotional Modulation

The primary aim of this study(14) was to investigate the potential effects of Kisspeptin-10 on limbic brain activity. Following administration of the peptide in experimental models, outcomes were assessed using neuroimaging techniques alongside psychometric evaluations.

The findings suggested that Kisspeptin-10 exposure was associated with increased activity within limbic brain regions. Additionally, the models appeared to demonstrate heightened responsiveness to sexual and bonding-related stimuli, indicating a possible influence of the peptide on emotional and behavioural processing within the limbic system.

Kisspeptin-10 and Reproductive Hormone Release

The primary objective of this study(15) was to evaluate the potential effects of Kisspeptin-10 on reproductive hormone release. The peptide was administered to both male and female experimental models to assess its influence on key gonadotropins.

In male subjects, results indicated that exposure to Kisspeptin-10 was associated with increased levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH). In female subjects, no significant changes in FSH or LH levels were observed across most phases of the menstrual cycle. However, during the preovulatory phase, elevations in both FSH and LH were reported, suggesting a phase-specific responsiveness to the peptide.

Kisspeptin-10 and Food Intake

Kisspeptin-10 is reported to be widely distributed across several brain regions, including the hippocampus, cerebellum, posterior hypothalamus, and septum. Given its presence in areas involved in appetite regulation—such as the arcuate nucleus (Arc) of the hypothalamus—researchers have explored its potential role in food intake. In one study,(11) adult male mice aged 6–8 weeks were maintained under standard conditions and provided with a normal diet and water. Both overnight-fasted and fed mice were administered varying concentrations of Kisspeptin-10 or a placebo. The findings suggested that, in fasted mice, the peptide may have reduced food intake during the initial 3–12-hour period, followed by an increase between 12–16 hours, ultimately resulting in similar overall intake compared to controls. These observations indicated a possible reduction in meal frequency and total feeding time, along with longer intervals between meals, while meal size and eating rate remained largely unchanged.

To further investigate these effects, additional studies examined the potential influence of Kisspeptin-10 on central appetite regulation. Researchers proposed that the peptide may affect gene expression linked to neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF), both of which are involved in appetite control. Experimental findings suggested that Kisspeptin-10 exposure may increase NPY gene expression while suppressing BDNF expression in hypothalamic cells (Hypo-E22). The peptide was also associated with reduced levels of neurotransmitters such as dopamine and serotonin (5-HT), while norepinephrine levels appeared unchanged. These reductions were reflected by increased ratios of their metabolites—dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin—following exposure. Collectively, these findings suggest that Kisspeptin-10 may influence feeding behaviour through central mechanisms involving neurotransmitter activity and gene expression related to appetite regulation.(12)

Studies in Impaired Kisspeptin-10 Systems

As part of this study,(13) the metabolic and energy-regulating role of Kisspeptin-10 was evaluated by comparing control mice with mice exhibiting impaired Kisspeptin signalling. The findings indicated that female mice with disrupted Kisspeptin systems showed marked increases in body weight and significantly impaired glucose tolerance. Interestingly, despite consuming less food than control females, these mice appeared more obese and demonstrated reduced locomotor activity and lower respiratory rates.

In contrast, no significant differences were observed between control male mice and male mice with impaired Kisspeptin systems. Both groups maintained normal body weight and glucose levels. These results suggest that disruptions in the Kisspeptin system may have sex-specific effects on metabolic regulation, particularly influencing energy balance and glucose handling in female models.

Kisspeptin-10 and Neuroprotection

The accumulation of amyloid-beta (Aβ) and alpha-synuclein (α-syn) within cholinergic neurons is considered to contribute to damage and dysfunction in key regions of the central nervous system. It has been proposed that Kisspeptin-10 may interact with Aβ at the cell surface, potentially reducing its harmful effects.(16) Experimental findings suggest that Kisspeptin-10 may counteract the toxicity associated with Aβ, prion protein (PrP), and islet amyloid polypeptide (IAPP), and that these effects may occur independently of antagonists targeting the kisspeptin receptor (GPR54) or neuropeptide FF (NPFF) receptors. Due to structural similarities between the non-amyloid-β component (NAC) of α-syn and the C-terminal region of Aβ, it has been hypothesised that Kisspeptin-10 may also mitigate α-syn-induced toxicity in cholinergic neurons.(17)

Research involving cholinergic cell models indicated that the effects of Kisspeptin-10 may be concentration-dependent. Higher concentrations appeared to increase cellular toxicity, whereas lower concentrations were associated with a reduction in toxicity induced by both wild-type and E46K mutant forms of α-syn. Computational modelling supported these findings by suggesting a stable interaction between Kisspeptin-10 and the C-terminal residues of α-syn, indicating a potentially meaningful molecular association.

Further investigation explored whether activation of the GPR54 receptor is necessary for these observed effects. In one study,(18) cholinergic SH-SY5Y neurons were engineered to express either wild-type or E46K mutant α-syn, and the effects of Kisspeptin-10 were assessed using flow cytometry and immunocytochemistry. The results suggested that Kisspeptin-10 may reduce apoptosis and mitochondrial damage in neurons affected by α-syn. Notably, these apparent protective effects were not diminished by the presence of a GPR54 antagonist (kisspeptin-234), indicating that the actions of Kisspeptin-10 may occur independently of GPR54 activation. Additionally, reductions in α-syn accumulation and choline acetyltransferase (ChAT) levels were observed in affected neurons, further supporting the peptide’s potential neuroprotective properties.

Kisspeptin-10 peptide is available for research and laboratory purposes only. Please speak to our friendly research team to find out more and for sourcing options.

References:

  1. Hypogonadotropic hypogonadism. US National Library of Medicine.  https://medlineplus.gov/ency/article/000390.htm

  2. KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)].  https://www.ncbi.nlm.nih.gov/gene/3814

  3. Hussain, Mehboob A et al. “There is Kisspeptin - And Then There is Kisspeptin.” Trends in endocrinology and metabolism: TEM vol. 26,10 (2015): 564-572. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587393/

  4. Pasquier, J., Kamech, N., Lafont, A., Vaudry, H., Rousseau, K., & Dufour, S. (2014). MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors, Journal of Molecular Endocrinology, 52(3), T101-T117.  https://jme.bioscientifica.com/view/journals/jme/52/3/T101.xml

  5. Messager, S., Chatzidaki, E. E., Ma, D., Hendrick, A. G., Zahn, D., Dixon, J., Thresher, R. R., Malinge, I., Lomet, D., Carlton, M. B., Colledge, W. H., Caraty, A., & Aparicio, S. A. (2005). Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1761–1766.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/

  6. Mead, E. J., Maguire, J. J., Kuc, R. E., & Davenport, A. P. (2007). Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. British journal of pharmacology, 151(8), 1143–1153.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/

  7. Rønnekleiv, O. K., & Kelly, M. J. (2013). Kisspeptin excitation of GnRH neurons. Advances in experimental medicine and biology, 784, 113–131.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/

  8. Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology. 2015;102(3):238-45. doi: 10.1159/000439133. Epub 2015 Aug 7.  https://pubmed.ncbi.nlm.nih.gov/26277870/

  9. Tng E. L. (2015). Kisspeptin signalling and its roles in humans. Singapore medical journal, 56(12), 649–656.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678402/

  10. Zeydabadi Nejad, S., Ramezani Tehrani, F., & Zadeh-Vakili, A. (2017). The Role of Kisspeptin in Female Reproduction. International journal of endocrinology and metabolism, 15(3), e44337.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/

  11. Stengel, A., Wang, L., Goebel-Stengel, M., & Taché, Y. (2011). Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport, 22(5), 253–257.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063509/

  12. Orlando G, Leone S, Ferrante C, Chiavaroli A, Mollica A, Stefanucci A, Macedonio G, Dimmito MP, Leporini L, Menghini L, Brunetti L, Recinella L. Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. Molecules. 2018 Nov 24;23(12):3071. doi: 10.3390/molecules23123071. PMID: 30477219; PMCID: PMC6321454.

  13. Kristen P. Tolson et.al, Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. The Journal of Clinical Investigation. Published June 17, 2014.  https://www.jci.org/articles/view/71075

  14. Chan, Y. M., Lippincott, M. F., Kusa, T. O., & Seminara, S. B. (2018). Divergent responses to kisspeptin in children with delayed puberty. JCI insight, 3(8), e99109.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121/

  15. Comninos, A. N., Wall, M. B., Demetriou, L., Shah, A. J., Clarke, S. A., Narayanaswamy, S., Nesbitt, A., Izzi-Engbeaya, C., Prague, J. K., Abbara, A., Ratnasabapathy, R., Salem, V., Nijher, G. M., Jayasena, C. N., Tanner, M., Bassett, P., Mehta, A., Rabiner, E. A., Hönigsperger, C., Silva, M. R., Dhillo, W. S. (2017). Kisspeptin modulates sexual and emotional brain processing in humans. The Journal of clinical investigation, 127(2), 709–719.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/

  16. Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 2012 Sep 19;3(9):706-19. doi: 10.1021/cn300045d. Epub 2012 May 30. PMID: 23019497; PMCID: PMC3447396.

  17. Simon, C., Soga, T., Ahemad, N., Bhuvanendran, S., & Parhar, I. (2022). Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro. International journal of molecular sciences, 23(9), 5193.   https://doi.org/10.3390/ijms23095193

  18. Simon, C., Soga, T., & Parhar, I. (2023). Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor- Independent Manner. International journal of molecular sciences, 24(7), 6056.   https://doi.org/10.3390/ijms24076056

Dr. Marinov

Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.

Kisspeptin-10 Peptide