Cardiogen (H-Ala-Glu-Asp-Arg-OH)^[1] is a short peptide classified as a bioregulator, primarily recognized for its potential influence on fibroblasts—cells responsible for tissue repair and scar formation. While initial research focused on its possible implications within the context of cardiovascular diseases, recent research suggests that Cardiogen’s action may extend beyond the cardiovascular system, indicating potential implications in other tissues.

Research suggests that the peptide may modulate fibroblast activity, which is considered to play a critical role in tissue repair and the extracellular matrix’s structural integrity. In particular, Cardiogen seems to have garnered attention for its ability to influence both collagen and elastin synthesis, two key components required for maintaining tissue integrity.

 

Mechanisms of Action

Cardiogen’s primary mechanism of action appears to involve possible regulatory effects on fibroblasts and cardiomyocytes. By stimulating fibroblast activity, the peptide appears to promote the synthesis of extracellular matrix components such as collagen, thereby believed to facilitate tissue regeneration and repair.^[2]
Interestingly, studies suggest that Cardiogen may modulate this fibroblast-driven tissue repair in multiple organs, and not only the cardiovascular system. Additionally, Cardiogen has been observed to possibly stimulate the proliferation of cardiac progenitor cells, leading to the regeneration of damaged myocardium, which may be crucial for restoring cardiac function.
In cardiovascular tissues, Cardiogen appears to support cardiomyocyte proliferation while inhibiting fibroblast-driven scar formation, a process deemed critical for mitigating adverse cardiac remodeling and heart failure in laboratory models. It may also downregulate p53 protein expression, potentially reducing apoptosis rates in cardiac cells and improving long-term outcomes in cardiovascular function.^[3]

 

Scientific and Research Studies

 

Cardiogen Peptide and Cardiac Tissue Regeneration

Research indicates that Cardiogen may play a significant role in cardiac tissue regeneration by promoting the proliferation of cardiomyocytes while inhibiting the growth and maturation of fibroblasts. This combination of action may lead to reduced scar formation, potentially improving the long-term prospects for cardiac remodeling and potentially preventing the progression to heart failure.

Furthermore, preliminary data suggests that Cardiogen may suppress the expression of the p53 protein, which is associated with apoptosis, thereby reducing the rate of programmed cell death in myocardial tissue. As indicated by the researchers, “The immunohistochemical study [indicated] a decrease of the p53 protein expression by cardiogen action. This [may] testify that cardiogen inhibits the apoptosis process in the myocard tissue.”^[3]

 

Cardiogen Peptide and Tumor Growth

Research suggests that the Cardiogen peptide may have differential effects on apoptosis regulation depending on the cell type. While it has been suggested to reduce apoptosis in cardiac cells by downregulating p53 expression, studies in rat models of M-1 sarcoma indicate that Cardiogen may potentially induce apoptosis in tumor cells. This effect appears to be concentration-dependent, underscoring its potential biological significance.^[4]

In particular, research conducted by Drs. Levdik and Knyazkin, affiliated with the St. Petersburg Institute of Bioregulation and Gerontology and the Russian Academy of Medical Sciences, has provided insight into Cardiogen’s influence on tumor growth. Their study on the “tumor-modifying effect of Cardiogen peptide in rats with transplanted M-1 sarcoma” revealed that Cardiogen exposure may have led to a significant increase in apoptosis within tumor cells compared to control groups. The concentration-dependent inhibition of M-1 sarcoma growth was attributed to the development of hemorrhagic necrosis and the stimulation of tumor cell apoptosis.

 

Cardiogen Peptide and Prostate Explorations

In vitro research has indicated that Cardiogen, along with a group of similar peptides, may regulate the expression of key signaling factors in prostate fibroblasts. These signaling factors are considered to be critical in creating a favorable microenvironment within tumors and may play a significant role in the development and progression of prostate cancer. Scientific data indicates that alterations in the synthesis of these markers may occur in cellular aging and senescent fibroblasts, disrupting the paracrine interactions between epithelial and associated stromal fibroblasts. As per the researchers, “These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.”^[5]

Studies in laboratory models suggest that Cardiogen has the potential to normalize or even support the levels of these signaling molecules in aging fibroblasts, aligning them with those found in youthful cell cultures. As per the study, “all the investigated peptides (including Cardiogen) possess the ability to actively enhance the expression of the above markers, whose synthesis significantly reduced in senescent cultures.”^[6]

This finding implies that Cardiogen may not only aid in the prevention of prostate cancer but also in controlling its progression. According to research by O.V. Kheifets and colleagues, these studies pave the way for developing peptide-based studies aimed at exploring age-related dysfunctions of the prostate gland.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 11583989, H-Ala-Glu-Asp-Arg-OH. https://pubchem.ncbi.nlm.nih.gov/compound/H-Ala-Glu-Asp-Arg-OH
2. Khavinson VK, Popovich IG, Linkova NS, Mironova ES, Ilina AR. Peptide Regulation of Gene Expression: A Systematic Review. Molecules. 2021 Nov 22;26(22):7053. doi: 10.3390/molecules26227053. PMID: 34834147; PMCID: PMC8619776. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619776/
3. Chalisova NI, Lesniak VV, Balykina NA, Urt’eva SA, Urt’eva TA, Sukhonos IuA, Zhekalov AN. [The effect of the amino acids and cardiogen on the development of myocard tissue culture from young and old rats]. Adv Gerontol. 2009;22(3):409-13. Russian. PMID: 20210190. https://pubmed.ncbi.nlm.nih.gov/20210190/
4. Levdik NV, Knyazkin IV. Tumor-modifying effect of cardiogen peptide on M-1 sarcoma in senescent rats. Bull Exp Biol Med. 2009 Sep;148(3):433-6. English, Russian. doi: 10.1007/s10517-010-0730-9. PMID: 20396706. https://pubmed.ncbi.nlm.nih.gov/20396706/
5. Begley L, Monteleon C, Shah RB, Macdonald JW, Macoska JA. CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro. Aging Cell. 2005 Dec;4(6):291-8. doi: 10.1111/j.1474-9726.2005.00173.x. PMID: 16300481. https://pubmed.ncbi.nlm.nih.gov/16300481/
6. Kheĭfets OV, Poliakova VO, Kvetnoĭ IM. [Peptidergic regulation of the expression of signal factors of fibroblast differentiation in the human prostate gland in cell aging]. Adv Gerontol. 2010;23(1):68-70. Russian. PMID: 20586252. https://pubmed.ncbi.nlm.nih.gov/20586252/

Matrixyl, chemically recognized as palmitoyl pentapeptide-3 (later renamed palmitoyl pentapeptide-4),^[1] is a synthetic lipopeptide composed of a fatty acid conjugated to a short chain of amino acids. Containing 5 amino acids (Lys-Thr-Thr-Lys-Ser-OH or KTTKS-OH), this peptide has a fatty acid portion that is speculated to support its lipid solubility, thereby potentially supporting ability to penetrate the stratum corneum and reach the dermal and epidermal layers.^[2]

Matrixyl peptide is suggested to function as an active ingredient in advanced research formulations, particularly the ones synthesized for anti-aging studies. Structurally, it is considered an isomer, meaning that it shares the same molecular formula as other peptides but exhibits distinct atomic arrangements. The primary bioactive component within Matrixyl, often referred to as “Micro-collagen,” is said to mimic the endogenous peptides that signal dermal repair, which has made Matrixyl a significant agent in dermal regeneration research.

Matrixyl has been developed through dermatological investigations focused on two key areas: the acceleration of wound healing and the mechanisms responsible for wrinkle formation.^[2] Over time, the dermatological ability to produce collagen, elastin, and fibronectin declines, resulting in a loss of structural integrity, elasticity, and hydration. Matrixyl, through its biochemical interactions, appears to restore these critical components of the stratum corneum, thus potentially contributing to the rejuvenation of the epidermal layer.

 

Mechanisms of Action

Matrixyl’s primary mechanism of action is suggested to be based on its hypothesized ability to promote the synthesis of extracellular matrix components, particularly collagen and fibronectin, within the dermal layer.^[2] The peptide interacts with fibroblasts, the key cells responsible for producing and remodeling the extracellular matrix. Research suggests that when exposed to Matrixyl, fibroblasts are stimulated via receptor-mediated signaling pathways, thereby enhancing their capacity to synthesize collagen, glycosaminoglycans (e.g., hyaluronic acid), and other relevant proteins.

The molecular action of Matrixyl is often compared to that of copper peptides, which also are frequently considered to stimulate dermatologic regeneration processes. However, Matrixyl uniquely activates a cascade of signaling events via a receptor-binding process that mimics the endogenous breakdown products of collagen. When collagen degrades, peptides called matrikines are released, which bind to receptors on fibroblasts, triggering the repair and remodeling of the stratum corneum matrix. Matrixyl appears to act similarly to these matrikines, particularly affecting collagen types I and IV. This stimulation may lead to increased production of these collagen types, which play essential roles in maintaining firmness and elasticity.^[3]

Moreover, the pentapeptide sequence (KTTKS) in Matrixyl is critical for its biological activity. The attached palmitoyl moiety serves as a lipid delivery system, allowing the peptide to penetrate the stratum corneum more thoroughly than water-soluble peptides. As a result, Matrixyl appears to support collagen synthesis, particularly type I collagen, which is the most abundant in the stratum corneum and provides structural support.^[3]

The peptide also appears to stimulate the production of fibronectin, a glycoprotein involved in cell adhesion and wound healing. Thus, it further reinforces the epidermal layer’s extracellular matrix. This comprehensive support of skin structure and function contributes to its wrinkle-reducing impacts.

 

Scientific and Research Studies

 

Matrixyl Peptide and Collagen Synthesis

In vitro studies have highlighted Matrixyl’s potential role in stimulating collagen synthesis.

One key study conducted on cultured fibroblasts revealed a substantial upregulation of collagen production following Matrixyl introduction by transmitting signals to fibroblasts and reportedly stimulating “feedback regulation of new collagen synthesis and ECM proteins.”^[4]

This research suggests that Matrixyl may significantly support the dermal layer’s ability to maintain its structural proteins, thereby potentially mitigating the visible impacts of cellular aging that impacts the stratum corneum. Further clinical studies support this data, showing that the implication of Matrixyl-containing formulations on research models led to measurable increases in collagen type I, the principal collagen form responsible for maintaining firmness.^[5] Collagen type I contributes to the epidermal layer’s tensile strength, and its synthesis is deemed critical for counteracting the thinning and fragility associated with cellular aging of skin cells.

Research has also indicated Matrixyl’s specific influence on collagen type IV synthesis. Collagen type IV appears to play a vital role in forming the basement membrane, which separates the epidermis from the dermis and supports overall skin structure. In a study evaluating the impacts of Matrixyl on dermal cells, collagen type IV synthesis appeared to increase significantly.

These findings indicate that Matrixyl might be a significant factor in reinforcing the structural layers of the dermis, potentially improving dermal resilience and reducing the depth of wrinkles.

 

Matrixyl Peptide and Wound Healing

Matrixyl’s origin is rooted in wound healing research, where it was initially explored for its potential to accelerate tissue repair.

In the cellular aging process, fibroblasts gradually lose their efficiency in generating new collagen, which may lead to delayed wound closure and compromise the integrity of the stratum corneum. As per the research, Matrixyl peptide “had a larger impact on wound healing compared to that in the positive control group,” suggesting that the peptide stimulates the fibroblast activity, showing potential in promoting the repair of damaged dermal and epidermal cells.^[2]

In another study,^[6] the potential influence of Matrixyl on fibroblast contractility and its role in scar formation was closely examined. The findings indicated that Matrixyl might functionally downregulate the expression of α-smooth muscle actin (α-SMA) and inhibit the trans-differentiation of fibroblasts into myofibroblasts. α-SMA is a protein predominantly expressed in smooth muscle cells, such as those found in blood vessels and visceral organs like the intestines and bladder. Myofibroblasts, a specialized cell type associated with wound healing and tissue repair, also express it.

In the context of fibrotic scarring, the upregulation of α-SMA in myofibroblasts is associated with increased collagen deposition, leading to the formation of excessive scar tissue. Matrixyl’s hypothetical ability to modulate α-SMA expression suggests its potential to limit myofibroblast differentiation, thereby reducing excessive collagen accumulation. This highlights its promise in attenuating fibrotic scarring and enhancing epidermal healing outcomes.

 

Matrixyl Peptide and Anti-Wrinkle Studies

In a notable clinical trial^[7] involving 93 female research models aged 35 to 55, the impacts of Matrixyl-infused moisturizer were compared to a placebo over 12 weeks. Matrixyl was applied to one side of the participants’ faces, while the placebo was applied to the other side. Results observed by researchers indicated that the Matrixyl-introduced group appeared to exhibit a significant reduction in both wrinkles and fine lines compared to the placebo group.

Periorbital wrinkles are a common biomarker associated with cellular aging, often resulting from repetitive movement of muscular tissue and the endogenous loss of elasticity in the stratum corneum. In a clinical study^[8] focusing on 21 female research models with visible periorbital creasing, Matrixyl, other peptides, and placebo were introduced exogenously to the periorbital area twice daily for eight weeks. Results suggested that the Matrixyl-introduced group appeared to significantly outperform both the groups introduced with placebo and other peptides.

Another investigation explored Matrixyl’s efficacy in improving overall epidermal smoothness and reducing the depth of periorbital wrinkles. This double-anonymized, randomized, controlled split-face study involved women aged 30 to 70 with moderate to severe periorbital wrinkles. After four weeks, participants in the Matrixyl-introduced group appeared to show more support for a reduction in wrinkle depth.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 58942400, Palmitoyl Pentapeptide-4. https://pubchem.ncbi.nlm.nih.gov/compound/Palmitoyl-Pentapeptide-4.
2. Kachooeian M, Mousivand Z, Sharifikolouei E, Shirangi M, Firoozpour L, Raoufi M, Sharifzadeh M. Matrixyl Patch vs Matrixyl Cream: A Comparative In Vivo Investigation of Matrixyl (MTI) Effect on Wound Healing. ACS Omega. 2022 Jul 11;7(28):24695-24704. doi: 10.1021/acsomega.2c02592. PMID: 35874243; PMCID: PMC9301720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301720/
3. Jones RR, Castelletto V, Connon CJ, Hamley IW. Collagen stimulating effect of peptide amphiphile C16-KTTKS on human fibroblasts. Mol Pharm. 2013 Mar 4;10(3):1063-9. doi: 10.1021/mp300549d. Epub 2013 Feb 4. PMID: 23320752. https://pubmed.ncbi.nlm.nih.gov/23320752/
4. Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy. Frontiers in chemistry, 8, 572923. https://doi.org/10.3389/fchem.2020.572923
5. Robinson LR, Fitzgerald NC, Doughty DG, Dawes NC, Berge CA, Bissett DL. Topical palmitoyl pentapeptide provides an improvement in photoaged human facial skin. Int J Cosmet Sci. 2005 Jun;27(3):155-60. doi: 10.1111/j.1467-2494.2005.00261.x. PMID: 18492182. https://pubmed.ncbi.nlm.nih.gov/18492182/
6. Park H, An E, Cho Lee AR. Effect of Palmitoyl-Pentapeptide (Pal-KTTKS) on Wound Contractile Process in Relation to Connective Tissue Growth Factor and α-Smooth Muscle Actin Expression. Tissue Eng Regen Med. 2017 Jan 19;14(1):73-80. https://link.springer.com/article/10.1007/s13770-016-0017-y
7. Robinson, L. R., Fitzgerald, N. C., Doughty, D. G., Dawes, N. C., Berge, C. A., & Bissett, D. L. (2005). Topical palmitoyl pentapeptide provides an improvement in photoaged human facial skin. International journal of cosmetic science, 27(3), 155–160. https://doi.org/10.1111/j.1467-2494.2005.00261.x
8. Aruan, R. R., Hutabarat, H., Widodo, A. A., Firdiyono, M. T. C. C., Wirawanty, C., & Fransiska, L. (2023). Double-blind, Randomized Trial on the Effectiveness of Acetylhexapeptide-3 Cream and Palmitoyl Pentapeptide-4 Cream for Crow’s Feet. The Journal of clinical and aesthetic dermatology, 16(2), 37–43. https://pubmed.ncbi.nlm.nih.gov/36909866/
9. Kaczvinsky, J. R., Griffiths, C. E., Schnicker, M. S., & Li, J. (2009). Efficacy of anti-aging products for periorbital wrinkles as measured by 3-D imaging. Journal of cosmetic dermatology, 8(3), 228–233. https://doi.org/10.1111/j.1473-2165.2009.00444.x

Lipopeptide (aka Palmitoyl hexapeptide-12 or Pal-VGVAPG) is a synthetic peptide derived from a fragment of the protein called elastin. Specifically, its peptide sequence is repeated several times in various forms of elastin, including tropoelastin. The peptide comprises a chain that includes the amino acids valine, glycine, alanine, proline, and glycine in the following sequence: valine-glycine-valine-alanine-proline-glycine (VGVAPG).^[1] In addition to this sequence, Lipopeptide is also palmitoylated. The inclusion of palmitic acid within the Lipopeptide structure is thought to support increased penetration to the deeper layers of various structures made of skin cells.

This peptide is posited to play a role in modulating fibroblast activity, possibly by interacting with specific receptors on the fibroblast membrane. Its mechanism is not fully understood, but research suggests it may stimulate the production of collagen and glycosaminoglycans while decreasing the synthesis of elastin, with chemotactic activity and metalloproteinase upregulation properties.^[2][3]

 

Mechanisms of Action

Lipopeptide may interact with fibroblasts, which are the primary cells responsible for producing key components of the extracellular matrix, such as elastin, collagen, glycosaminoglycans (like hyaluronan), proteoglycans, fibronectin, and laminin. In particular, Lipopeptide is believed to upregulate the production of collagen while suppressing elastin production.^[4] Collagen is a major protein believed to provide strength and resilience in connective tissues such as the skin. The reduction in elastin may be due to negative feedback regulation related to the sequence of Lipopeptide, which is a repetitive sequence found in the structure of elastin fibers like tropoelastin.^[2]

Tropoelastin is considered to be a soluble precursor protein to elastin, an essential component of the extracellular matrix that provides elasticity to various tissues, such as skin, lungs, arteries, and ligaments. Further, researchers report that “The present study clearly [indicated] that the hexapeptide VGVAPG stimulated skin fibroblast proliferation.”^[2] Thus, in addition to possibly regulating the function of fibroblast cells, Lipopeptide is also studied for its potential to upregulate the production of new fibroblast cells. Researchers are also investigating if Lipopeptide may interact with the function of the pigment-producing skin cells called melanocytes and the production of inflammatory molecules by fibroblasts in different conditions.

 

Scientific and Research Studies

 

Lipopeptide and Skin Fibroblasts

Lipopeptide is believed to act as a chemoattractant for fibroblasts, guiding these cells, as well as immune cells such as monocytes, to areas where repair or regeneration may be necessary. Specifically, the VGVAPG sequence is considered to be a key sequence driving the chemotactic activity. Researchers also posit that the interaction of VGVAPG with fibroblasts may not only encourage cell migration but potentially plays a role in tissue remodeling processes. Further, studies suggest that the responsiveness of fibroblasts to VGVAPG is apparently dependent on their differentiation status. Specifically, undifferentiated fibroblasts, which are incapable of producing elastin, do not appear to exhibit chemotaxis toward VGVAPG or other elastin-derived peptides. However, upon exposure to extracellular matrix material and subsequent induction of elastin synthesis, these cells become responsive, indicating that the ability to synthesize elastin might be necessary for fibroblast chemotaxis toward VGVAPG, which allows the peptide to attract only mature and functional cells.^[5]

Another study suggests that thanks to its VGVAPG sequence, Lipopeptide appears to potentially stimulate the proliferation of fibroblasts. The mechanism of action is suggested to involve a binding event between VGVAPG and unknown plasmalemmal receptors on the fibroblast cells’ membranes. Although the exact receptor has not been fully characterized, it is hypothesized that this binding initiates a signaling cascade that results in fibroblast proliferation. The study implies that there is a lag phase observed before proliferation which may depend on the initial fibroblast density, suggesting that the response to VGVAPG might be density-dependent. Moreover, when fibroblasts are exposed to VGVAPG, they possibly undergo morphological changes, becoming more elongated. This might imply that VGVAPG not only stimulates proliferation but may also potentially influence the cellular architecture of fibroblasts under these conditions.^[6]

 

Lipopeptide and Skin Inflammation Markers

Lipopeptides have been proposed to modulate the production of proinflammatory mediators by skin cells, including interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), which may, in turn, slow the degradation of the skin’s extracellular matrix.^[7] In particular, some in vitro studies suggest that lipopeptides might reduce IL-6 production in keratinocytes, the primary cell type of the epidermis, and in fibroblasts. IL-6 is suggested to be a key regulator of inflammation, a necessary biological response for cell repair following injury or stress. However, excessive or prolonged IL-6 production has been linked to chronic inflammation, which may contribute to the breakdown of the skin’s structural integrity. This is thought to occur through the stimulation of matrix metalloproteinases (MMPs), a group of enzymes that degrade extracellular matrix proteins like collagen and elastin. Overactivation of MMPs, particularly under conditions such as skin cell exposure to ultraviolet (UV) radiation, may lead to diminished skin tissue elasticity, reduced firmness, and other visible signs of skin cell aging. By potentially modulating IL-6 levels, Lipopeptide may influence MMP activity and thus play a role in maintaining the structural integrity of the skin’s extracellular matrix. This reduction in MMP-mediated degradation may hypothetically help preserve collagen and elastin, which are considered essential for skin cell integrity as well as tissue elasticity and resilience.^[8][9]

 

Lipopeptide and Skin Pigmentation

Lipopeptide has been posited to interact with melanocytes by modulating melanogenesis-related pathways. A study suggests that Lipopeptide has been “identified as major inhibitors of melanogenesis based on their gene expression profiles.” Specifically, it may downregulate the expression of multiple melanogenic genes in melanocytes. This downregulation may potentially influence critical proteins involved in melanogenesis, such as MITF (microphthalmia-associated transcription factor), tyrosinase, and dopachrome tautomerase. These proteins are essential for the regulation of melanin production, and their inhibition might lead to decreased melanin synthesis.

Additionally, Lipopeptide possibly exerts its actions through the phosphorylation of ERK, which may contribute to the degradation of MITF, leading to reduced melanogenic activity. The gene expression studies in melanocytes showed a notable downregulation of these pathways after exposure to Lipopeptide, suggesting a direct interaction that might decrease melanin production in melanocytes. Furthermore, an in vitro melanogenic model suggested that Lipopeptide apparently resulted in a marked decrease in melanin production, as detailed by absorbance readings indicating reduced melanin content.^[10] Interventional studies of Lipopeptide on skin cell aging have also suggested that this peptide may have increased skin structure firmness by 20% and improved epidermal tone by 33 % compared to controls.^[9]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. Resende, D. I. S. P., Ferreira, M. S., Sousa-Lobo, J. M., Sousa, E., & Almeida, I. F. (2021). Usage of Synthetic Peptides in Cosmetics for Sensitive Skin. Pharmaceuticals (Basel, Switzerland), 14(8), 702. https://doi.org/10.3390/ph14080702
2. Tajima, S., Wachi, H., Uemura, Y., & Okamoto, K. (1997). Modulation by elastin peptide VGVAPG of cell proliferation and elastin expression in human skin fibroblasts. Archives of dermatological research, 289(8), 489–492. https://doi.org/10.1007/s004030050227
3. Errante, F., Ledwoń, P., Latajka, R., Rovero, P., & Papini, A. M. (2020). Cosmeceutical peptides in the framework of sustainable wellness economy. Frontiers in chemistry, 8, 572923.
4. Husein El Hadmed, H., & Castillo, R. F. (2016). Cosmeceuticals: peptides, proteins, and growth factors. Journal of cosmetic dermatology, 15(4), 514–519. https://doi.org/10.1111/jocd.12229
5. Senior, R. M., Griffin, G. L., Mecham, R. P., Wrenn, D. S., Prasad, K. U., & Urry, D. W. (1984). Val-Gly-Val-Ala-Pro-Gly, a repeating peptide in elastin, is chemotactic for fibroblasts and monocytes. The Journal of cell biology, 99(3), 870–874. https://doi.org/10.1083/jcb.99.3.870
6. Kamoun, A., Landeau, J. M., Godeau, G., Wallach, J., Duchesnay, A., Pellat, B., & Hornebeck, W. (1995). Growth stimulation of human skin fibroblasts by elastin-derived peptides. Cell adhesion and communication, 3(4), 273–281. https://doi.org/10.3109/15419069509081013
7. Ngoc, L. T. N., Moon, J. Y., & Lee, Y. C. (2023). Insights into bioactive peptides in cosmetics. Cosmetics, 10(4), 111.
8. Schagen, S. K. (2017). Topical peptide treatments with effective anti-aging results. Cosmetics, 4(2), 16.
9. Veiga, E., Ferreira, L., Correia, M., Pires, P. C., Hameed, H., Araújo, A. R., … & Paiva-Santos, A. C. (2023). Anti-aging peptides for advanced skincare: focus on nanodelivery systems. Journal of Drug Delivery Science and Technology, 105087.
10. Widgerow, A., Wang, J., Ziegler, M., Fabi, S., Garruto, J., Robinson, D., & Bell, M. (2022). Advances in Pigmentation Management: A Multipronged Approach. Journal of drugs in dermatology : JDD, 21(11), 1206–1220. https://doi.org/10.36849/JDD.7013

Kisspeptin-10, an endogenously occurring peptide, is derived from the KISS1 gene. The original 145-amino acid polypeptide undergoes proteolytic cleavage to yield a smaller peptide comprised of 54 amino acids. This 54-amino acid peptide is further processed into Kisspeptin 45-54, commonly referred to as Kisspeptin-10.^[1,2]

The KISS1 gene has been identified as a potential suppressor of metastasis in melanomas and breast carcinomas. This may suggest potential impacts on the inhibition of abnormal cell proliferation.^[1] Initially recognized for its potential in metastasis suppression, subsequent research proposed that Kisspeptin-10 may hypothetically impact the hypothalamus and pituitary gland. This may imply some impact on the regulation of systems related to reproduction. Independent studies conducted in the mid-2000s suggest it may be possible for Kisspeptin-10 to be involved in hypogonadotropic hypogonadism. This may be particularly true in its capacity as a ligand for the G-protein coupled receptor 54 (GPR54).^[3]

 

Mechanism of Action

Hypogonadotropic hypogonadism is characterized by inadequate or absent sex hormone production. This may be due to dysfunction in the pituitary gland, hypothalamus, or other parts of the brain. Gonadotropin-releasing hormone (GnRH) is considered to play a pivotal role in stimulating the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are integral to various reproductive functions. Deficiencies in GnRH, FSH, and LH are identified as key contributors to hypogonadotropic hypogonadism.^[4]

The GPR54 receptor also referred to as the KISS1 receptor (KISS1R), has been identified as a critical GnRH receptor.^[4] Kisspeptin-10 is hypothesized to bind to GPR54 receptors, which may potentially activate the reproductive axis through the stimulation of GnRH and gonadotropin neurons.^[5]

Research has isolated smaller peptide fragments, such as Kisspeptin-10, Kisspeptin-13, and Kisspeptin-14, which may exhibit biological activity towards GPR54. These peptides are proposed to bind with low affinity to GPR54 receptors, which may induce calcium mobilization, arachidonic acid release, and extracellular protein kinase phosphorylation. Such events may eventually lead to the depolarization of Kisspeptin-10 neurons and may ultimately contribute to gonadotropin release.

Ongoing research has posited several potential mechanisms of action for Kisspeptin-10. This includes the peptide’s possible role in stimulating GnRH release. The peptide may support endogenous gonadotropin release in animal models with reduced fertility. Also, the peptide may induce desensitization and suppression of the hypothalamus-pituitary-gonadal axis under certain conditions.^[6]

 

Scientific and Research Studies

 

Kisspeptin-10 Peptide and Delayed Hormonal Development

The primary aim of this referenced scientific study^[7] was to investigate the observed impacts of Kisspeptin-10 peptide in research models with delayed hormonal development.

In this study, researchers hypothesized that Kisspeptin-10 may stimulate gonadal hormone release and modulate reproductive function in laboratory test models. The study involved the random introduction of either Kisspeptin-10 or gonadotropin-releasing hormone (GnRH) to the test models.

Luteinizing hormone (LH) levels were monitored overnight following the introduction. Subsequently, all test models were exposed to GnRH for six days, after which LH levels were re-evaluated. The results observed by researchers indicated that 47% of the experimental group exposed to Kisspeptin-10 exhibited increased LH levels. An additional 6% of the group exhibited an intermediate response, while the remaining 47% indicated no change after exposure to the peptide.

 

Kisspeptin-10 Peptide and Reproductive Regulation

A comprehensive literature review conducted in 2017 examined articles published between 1999 and 2016. This review suggested that experimental data might support the hypothesis that the Kisspeptin-10 system—including the KISS1 gene and its associated GPR54 receptors—might potentially regulate the release of gonadotropin hormones. Researchers suggest that “Kisspeptin or its receptor represents a potential therapeutic target in… [test models] with fertility disorders.”^[8]

Studies conducted on experimental animal models suggested that reproductive disorders like HH and PCOS might be linked to abnormalities within the KISS1 and GPR54 systems. The findings of this literature review indicated that Kisspeptin-10 may potentially function as a neuropeptide regulator of GnRH release.

 

Kisspeptin-10 Peptide and Reproductive Hormone Release

The objective of the study^[9] was to explore the potential influence of Kisspeptin-10 on the secretion of reproductive hormones. Kisspeptin-10 was introduced to both male and female test models. The findings indicate that in male test models, exposure to the peptide may lead to an elevation in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. In contrast, female test models did not exhibit significant changes in FSH and LH levels throughout the menstrual cycle. Comparatively, there was a notable increase in the hormone levels of observed female test models during the preovulatory phase.

 

Kisspeptin-10 and Its Influence on Food Intake

Kisspeptin-10 appears to be widely distributed across various brain regions, including the hippocampus, cerebellum, posterior hypothalamus, and septum. Its presence in key nuclei involved in food intake regulation, such as the arcuate nucleus (Arc) within the hypothalamus, prompted an investigation into its potential impacts on the feeding behavior of murine test models.

An experiment^[10] involving adult male murine models, aged 6 to 8 weeks and maintained under standard conditions, assessed the impact of Kisspeptin-10 on food intake. Following an overnight fast, the murine models were exposed to varying concentrations of Kisspeptin-10 or a placebo alongside a standard rodent diet and water.

Results from this study suggest that Kisspeptin-10 introduction in overnight-fasted mice led to a reduction in caloric intake during the initial 3-to-12-hour period. However, caloric intake reportedly increased during the subsequent 12-to-16-hour period, eventually aligning with levels observed in the placebo group of laboratory test models. This suggests that Kisspeptin-10 may “be a negative central regulator of feeding by increasing satiety.” Scientists observed that exposure to the peptide may lead to increased intervals between periods of calorie consumption without significant change to caloric intake.

Further research^[11] has explored Kisspeptin-10’s potential impacts on caloric intake regulation within the central nervous system (CNS). Investigations have suggested that the peptide may influence the expression of genes associated with neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Additionally, Kisspeptin-10 may affect neurotransmitter concentrations, including dopamine, norepinephrine, serotonin (5-hydroxytryptamine or 5-HT), dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid in hypothalamic cells (specifically Hypo-E22 cells). Observations indicate that Kisspeptin-10 might support NPY gene expression while suppressing BDNF expression.

The peptide also appears to reduce serotonin and dopamine levels, with norepinephrine concentrations remaining stable. Notably, this reduction in dopamine and serotonin was accompanied by increased ratios of their metabolites—dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin—following Kisspeptin-10 exposure. The observed changes in NPY and BDNF expression, coupled with alterations in serotonin activity, may suggest a potential role for Kisspeptin-10 in influencing hunger hormone signaling.

 

Kisspeptin-10 and Emotional Impacts

The study aimed to investigate the impacts of Kisspeptin-10 on limbic brain activity.^[12] Neuroimaging and psychometric assessments were employed to analyze the impact of Kisspeptin-10 exposure in research models. The findings suggest that Kisspeptin-10 may have influenced limbic brain function, with data suggesting heightened responsiveness to mating and bonding stimuli.

 

Kisspeptin-10 and Neuroprotection

The accumulation of amyloid-beta (Aβ) and alpha-synuclein (α-syn) in cholinergic neurons is associated with damage and dysfunction in critical central nervous system structures. It is hypothesized that Kisspeptin-10 may bind to extracellular Aβ, potentially mitigating its harmful impacts. Studies^[13] indicate that Kisspeptin-10 may counteract the detrimental actions of Aβ, prion protein (PrP), and Islet Amyloid Polypeptide (IAPP) without interference from antagonists of the kisspeptin receptor (GPR-54) or the neuropeptide FF (NPFF) receptor. The similarity between the non-amyloid-β component (NAC) of α-syn and the C-terminus of Aβ raises the possibility that Kisspeptin-10 might also reduce α-syn-induced toxicity in cholinergic neurons.

Research^[14] involving cholinergic cells suggests that while high concentrations of Kisspeptin-10 may increase toxicity, lower concentrations might decrease toxicity associated with both wild-type and E46K mutant forms of α-syn. Computational studies support these findings, and some suggest a potentially significant interaction between Kisspeptin-10 and the C-terminal residues of α-syn. Molecular dynamics simulations indicate that the complexes formed between Kisspeptin-10 and α-syn indicate substantial stability.

Further investigation^[15] has focused on whether GPR54 activation is crucial for Kisspeptin-10’s ability to bind to the C-terminal regions of α-syn. One study observed choline acetyltransferase (ChAT)-positive SH-SY5Y neurons, genetically modified to express either wild-type or E46K mutant α-syn, to evaluate the impact of Kisspeptin-10 on neuronal damage through flow cytometry and immunocytochemistry.

Some findings suggest that Kisspeptin-10 may reduce both apoptosis and mitochondrial damage in neurons affected by α-syn, with its protective impacts remaining unaffected by the presence of a GPR54 antagonist, kisspeptin-234 (KP-234). This implies that GPR54 activation might not be necessary for Kisspeptin-10’s neuroprotective impacts. Additionally, Kisspeptin-10 appears to lower the levels of α-syn and ChAT in neurons overexpressing both wild-type and E46K mutant α-syn.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)]. https://www.ncbi.nlm.nih.gov/gene/3814
2. Mead EJ, Maguire JJ, Kuc RE, Davenport AP. Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer, and the cardiovascular system. Br J Pharmacol. 2007 Aug;151(8):1143-53. doi: 10.1038/sj.bjp.0707295. Epub 2007 May 21. PMID: 17519946; PMCID: PMC2189831. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/
3. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6. doi: 10.1073/pnas.0409330102. Epub 2005 Jan 21. PMID: 15665093; PMCID: PMC545088. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/
4. Hypogonadotropic hypogonadism. US National Library of Medicine. https://medlineplus.gov/ency/article/000390.htm
5. Rønnekleiv OK, Kelly MJ. Kisspeptin excitation of GnRH neurons. Adv Exp Med Biol. 2013;784:113-31. doi: 10.1007/978-1-4614-6199-9_6. PMID: 23550004; PMCID: PMC4019505. target=”_blank” rel=”noopener”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/
6. Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology. 2015;102(3):238-45. doi: 10.1159/000439133. Epub 2015 Aug 7. PMID: 26277870. https://pubmed.ncbi.nlm.nih.gov/26277870/
7. 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
8. Zeydabadi Nejad S, Ramezani Tehrani F, Zadeh-Vakili A. The Role of Kisspeptin in Female Reproduction. Int J Endocrinol Metab. 2017 Apr 22;15(3):e44337. doi: 10.5812/ijem.44337. PMID: 29201072; PMCID: PMC5702467. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/
9. Comninos AN, Wall MB, Demetriou L, Shah AJ, Clarke SA, Narayanaswamy S, Nesbitt A, Izzi-Engbeaya C, Prague JK, Abbara A, Ratnasabapathy R, Salem V, Nijher GM, Jayasena CN, Tanner M, Bassett P, Mehta A, Rabiner EA, Hönigsperger C, Silva MR, Brandtzaeg OK, Lundanes E, Wilson SR, Brown RC, Thomas SA, Bloom SR, Dhillo WS. Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest. 2017 Feb 1;127(2):709-719. doi: 10.1172/JCI89519. Epub 2017 Jan 23. PMID: 28112678; PMCID: PMC5272173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/
10. 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/
11. Orlando G, Leone S, Ferrante C, Chiavaroli A, Mollica A, Stefanucci A, Macedonio G, Dimmito MP, Leporini L, Menghini L, Brunetti L, Recinella L. s 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321454/
12. Chan YM, Lippincott MF, Kusa TO, Seminara SB. Divergent responses to kisspeptin in children with delayed puberty. JCI Insight. 2018 Apr 19;3(8):e99109. doi: 10.1172/jci.insight.99109. PMID: 29669934; PMCID: PMC5931121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121/
13. 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. https://pubmed.ncbi.nlm.nih.gov/23019497/
14. 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
15. 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
16. Image Source: https://pubchem.ncbi.nlm.nih.gov/compound/Kisspeptin-10

Vialox, also known as Pentapeptide-3v, is a synthetic peptide characterized by the amino acid sequence GPRPA.^[1] This molecule is posited to function through the inhibition of neuronal nicotinic acetylcholine receptors located within the postsynaptic membrane of muscle cells. These receptors are deemed responsible for the transmission of signals from nerve cells to muscle cells, which subsequently results in muscle contraction.

By potentially diminishing the release of acetylcholine, Vialox may contribute to muscle relaxation, thereby possibly reducing the depth and formation of wrinkles along the skin barrier. The proposed mechanism of action for Vialox bears resemblance to that of tubocurarine, a natural alkaloid compound known for its muscle-relaxing properties.

 

Scientific and Research Studies

 

Action Mechanisms

Vialox is suggested by researchers to inhibit neurotransmitter activity.^[2] It may function similarly to tubocurarine through its interaction with acetylcholine receptors on the postsynaptic membrane of muscle cells.^[3] Tubocurarine, a naturally occurring alkaloid found in the bark of plants such as Chondrodendron tomentosum (commonly known as “curare”), is considered a potent neurotoxin. It acts as a non-depolarizing neuromuscular blocker by preventing acetylcholine from inducing muscle contraction at the neuromuscular junction.

Researchers also classify Vialox as a non-depolarizing neuromuscular blocker. The peptide binds to acetylcholine receptors on the postsynaptic membrane of muscle cells, acting as “a competitive antagonist” at these receptor sites.^[4] It may interact with neuronal nicotinic acetylcholine receptors, which play a role in regulating muscle contraction by mediating communication between motor nerves and muscles at the neuromuscular junction.

As an antagonist, Vialox appears to block acetylcholine binding to these receptors, preventing the opening of sodium ion channels required for depolarizing the cell and initiating muscle contraction.^[5] By inhibiting acetylcholine receptor activity, Vialox may potentially keep smooth muscles relaxed, possibly reducing wrinkles in the skin barrier as a result.

 

Vialox Peptide and Wrinkle Formation, Skin Texture

Research into Vialox has explored its potential to mitigate wrinkles on the skin surface and decrease texture variations along the skin barrier. The study of compounds in wrinkle reduction carries certain risks, particularly with higher concentrations or prolonged exposure. Long-term exposure may also pose unknown or unanticipated ancillary impacts within the laboratory test models. However, Vialox is noted for its short half-life and potential for less abrasive impacts. Studies suggest that this compound may cause “softened wrinkles and reduced skin roughness.”^[5]

Experimental data indicated a reduction in muscle contractions by 71% within one minute of Vialox exposure, with a subsequent 58% reduction observed after two hours. These findings imply that the decreased frequency of muscle contractions may contribute to the formation of shallower lines on the skin’s surface.

Additional research supports Vialox’s potential in reducing the development and depth of skin wrinkles.^[7] Results indicate a 49% decrease in wrinkle size and a 47% reduction in skin roughness after 28 days of consistent exposure.

 

Vialox Peptide and Neuromuscular Transmission

Vialox has garnered scientific interest due to its proposed ability to disrupt nerve-muscle communication. Unlike other antagonists of nicotinic acetylcholine receptors (AChR), Vialox appears to act exclusively on peripheral AChR, with minimal impact on central neuronal receptors as suggested by animal studies. Researchers hypothesize that Vialox might be effective in addressing certain spastic conditions, including migraines and muscle spasms.

Vialox is suggested to interfere with signal transmission between neurons and muscles by acting as an antagonist of the acetylcholine receptor. It appears to block nerve signals at the post-synaptic membrane, leading to muscle relaxation. Normally, when a nerve’s axon releases acetylcholine, these signals travel to the neuromuscular junction and bind to receptors on the muscle, facilitating the release of sodium ions. This process may result in depolarization, generating the electrical pulse responsible for muscle contraction and wrinkle formation.

Vialox is studied for its potential to halt this process by binding to AChR, thereby preventing acetylcholine from attaching to these receptors. This blockade is thought to reduce both the frequency and intensity of muscular contractions, similar to the effects induced by botulinum toxin, tubocurarine, and curare toxin. The consequent partial paralysis of muscles leads to forced relaxation.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. National Center for Biotechnology Information (2024). PubChem Compound Summary for CID 67073230, Vialox. Retrieved August 4, 2024 from https://pubchem.ncbi.nlm.nih.gov/compound/Vialox.
2. Husein el Hadmed, H., & Castillo, R. F. (2016). Cosmeceuticals: peptides, proteins, and growth factors. Journal of cosmetic dermatology, 15(4), 514-519. Husein el Hadmed, H., & Castillo, R. F. (2016). Cosmeceuticals: peptides, proteins, and growth factors. Journal of cosmetic dermatology, 15(4), 514-519. https://pubmed.ncbi.nlm.nih.gov/27142709/
3. Lupo, M. P., & Cole, A. L. (2007). Cosmeceutical peptides. Dermatologic therapy, 20(5), 343-349. https://pubmed.ncbi.nlm.nih.gov/18045359/
4. Gorouhi, F., & Maibach, H. I. (2009). Role of peptides in preventing or treating aged skin. International journal of cosmetic science, 31(5), 327-345. https://pubmed.ncbi.nlm.nih.gov/19570099/
5. Satriyasa B. K. (2019). Botulinum toxin (Botox) A for reducing the appearance of facial wrinkles: a literature review of clinical use and pharmacological aspect. Clinical, cosmetic and investigational dermatology, 12, 223–228. https://doi.org/10.2147/CCID.S202919
6. Kalandakanond, S., & Coffield, J. A. (2001). Cleavage of SNAP-25 by botulinum toxin type A requires receptor-mediated endocytosis, pH-dependent translocation, and zinc. The Journal of pharmacology and experimental therapeutics, 296(3), 980–986. https://pubmed.ncbi.nlm.nih.gov/11181932/
7. Reddy BY, Jow T, Hantash BM. Bioactive oligopeptides in dermatology: Part II. Exp Dermatol. 2012 Aug;21(8):569-75. doi: 10.1111/j.1600-0625.2012.01527.x. Epub 2012 Jun 4. PMID: 22672721. https://pubmed.ncbi.nlm.nih.gov/22672721/
8. Lebedev DS, Kryukova EV, Ivanov IA, Egorova NS, Timofeev ND, Spirova EN, Tufanova EY, Siniavin AE, Kudryavtsev DS, Kasheverov IE, Zouridakis M, Katsarava R, Zavradashvili N, Iagorshvili I, Tzartos SJ, Tsetlin VI. Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors. Mol Pharmacol. 2019 Nov;96(5):664-673. doi: 10.1124/mol.119.117713. Epub 2019 Sep 6. PMID: 31492697. https://pubmed.ncbi.nlm.nih.gov/31492697/

Retatrutide, also known by the identifier LY3437943, is a synthetic peptide characterized as a triple receptor agonist, comprising a sequence of 39 amino acids.^[1]

Designed as an analog to gastric inhibitory polypeptide (GIP), this compound reportedly exhibits additional affinity towards the glucagon-like peptide-1 (GLP-1) receptor and the glucagon (GCG) receptor.^[2] These receptors typically bind to their respective endogenous hormones, GIP, GLP-1, and GCG, which function as key hormonal regulators within the endocrine system. It is proposed that GLP-1 and GIP, acting as incretin hormones, might enhance insulin secretion from pancreatic beta cells and potentially increase satiety following nutrient intake. Conversely, glucagon is thought to play a compensatory role by potentially elevating blood glucose levels during fasting states.

Moreover, activation of GLP-1 receptors is suggested to slow gastric emptying, while stimulation of GCG receptors is hypothesized to increase energy expenditure and fat metabolism, notably influencing hepatic processes and converting white adipose tissue to beige adipose tissue, which is believed to possess thermogenic properties similar to brown adipose tissue, thereby potentially enhancing thermogenesis and metabolic rates.

The interaction of Retatrutide with these receptors indicates a multifaceted impact on metabolic regulation, which may be significant in the study of glycemic control and weight management. Additionally, Retatrutide has undergone chemical modification with a C20 moiety, purportedly extending its half-life to approximately six days.^[3]

 

Scientific and Research Studies

 

Retatrutide Peptide and Glycated Hemoglobin Levels

Retatrutide has indicated potential in reducing glycated hemoglobin (HbA1c) levels in models of hyperglycemia and baseline HbA1c exceeding 7%. Data from phase 2 trials lasting up to 36 weeks suggest that Retatrutide may decrease HbA1c levels by as much as 2.16% (23.59 mmol/mol), indicating a significant amelioration of hyperglycemia. The findings also highlighted a notable reduction in total weight, with decreases from baseline to 36 weeks reaching up to a least-squares mean of 16.94% in the Retatrutide-exposed groups.^[4]

 

Retatrutide Peptide and Appetite and Energy Intake

In a 48-week phase 2 study, Retatrutide has been investigated for its potential to significantly reduce total energy intake and facilitate the maintenance of a caloric deficit.

The research suggests that Retatrutide may lead to a substantial reduction in baseline weight, with observed decreases exceeding 24.2%, compared to a 2.1% reduction observed in the control group. Additionally, the study reported improvements in several cardiometabolic parameters, including indicators related to cholesterol metabolism, glucose regulation, and insulin sensitivity.^[5]

Researchers noted that in type 2 diabetes models, Retatrutide peptide showed “meaningful improvements in glycaemic control and robust reductions in bodyweight, with a […] profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists.”

 

Retatrutide Peptide and GIP Receptors Interaction

Retatrutide’s mechanism of action includes the activation of gastric inhibitory polypeptide (GIP) receptors. A comprehensive study has investigated the possible intricate roles of GIP receptor activation in the regulation of energy balance. Researchers hypothesize that Retatrutide may exert influence through central neural pathways, particularly in key brain regions such as the hypothalamus and brainstem^[6], which are considered critical for maintaining energy homeostasis and appetite. It is proposed that GIP receptor agonists may directly interact with neurons in these regions, potentially altering neuronal activity to reduce caloric intake and promote a negative energy balance.

The hypothalamus, a regulator in this process, contains specific nuclei—such as the arcuate, paraventricular, and ventromedial nuclei—that are believed to be essential in the regulation of appetite and energy expenditure. Activation of GIP receptors within these nuclei may suppress appetite or enhance signals of satiety. For example, GIP receptor activation in the arcuate nucleus might modulate neurons producing neuropeptide Y (NPY), which is associated with increased appetite, and pro-opiomelanocortin (POMC), which is linked to appetite suppression. This suggests that GIP receptor agonists might influence these neuropeptide systems, potentially leading to reduced caloric intake.

Moreover, the study explores the potential impact of GIP receptor agonists on the brain’s emetic centers. By potentially modulating neural circuits in the area postrema and the nucleus tractus solitarius of the brainstem—key areas involved in nausea and vomiting—GIP receptor agonists might inhibit these responses. Additionally, the role of GIP receptor agonists in enhancing the permeability of the blood-brain barrier (BBB) is proposed as a mechanism to improve the delivery and efficacy of agents targeting brain regions involved in energy balance. This may involve the modulation of tight junctions or transport systems within the neurovascular unit, facilitating increased access of these agents to the central nervous system (CNS).

 

Retatrutide Peptide and Energy Metabolism

Activation of glucagon (GCG) receptors by agonists such as Retatrutide may promote increased energy expenditure and fat oxidation, potentially enhancing energy utilization. Studies suggest that Retatrutide may activate GCG receptors in hepatocytes, possibly boosting energy expenditure by increasing lipid catabolism and enhancing the liver’s metabolic rate. This might be facilitated through mechanisms such as hepatic futile cycling, enhanced mitochondrial function, and the secretion of thermogenic agents such as fibroblast growth factor 21 (FGF21) and bile acids, which may further augment energy expenditure. The activation of GCG receptors in the liver by Retatrutide may trigger a cascade of metabolic events that induce weight loss, including the reduction of hepatic steatosis through increased lipid oxidation, elevated activity of metabolic enzymes, and upregulation of mitochondrial biogenesis.^[7] Key hormones like FGF21 and bile acids, released by the liver in response to GCG receptor activation, might play a role in systemic energy homeostasis.

Retatrutide may also stimulate GCG receptors in adipocytes, initiating a process known as beiging, which transforms white adipocytes into beige adipocytes. Beige adipocytes, similar to brown adipocytes, may contribute to increased caloric expenditure by generating heat, potentially enhancing thermogenesis and metabolic rate. The beiging of white adipose tissue may involve the induction of UCP1-dependent non-shivering thermogenesis and metabolic futile cycles, such as the creatine and succinate cycles, which may dissipate energy as heat. Additionally, Retatrutide might upregulate the expression of thermogenic genes in both brown and beige adipocytes, promoting the formation and activity of these thermogenically active cells.

Furthermore, Retatrutide’s activation of GCG receptors may extend to enhancing the thermogenic capacity of brown adipose tissue (BAT). Activation of BAT by Retatrutide may increase metabolic rate through uncoupling protein 1 (UCP1), which may dissipate the mitochondrial proton gradient as heat. This process might utilize stored lipids and support the oxidation of circulating glucose, lipids, and amino acids, contributing to overall energy expenditure. Based on this research, the researchers propose that “the thermogenic activity of GCGR agonism” may assist “in lowering weight.”

 

Retatrutide Peptide and Metabolic Influence

Research posits that Retatrutide may exert its effects through the activation of glucagon-like peptide-1 (GLP-1) receptors, which are typically ubiquitous. This peptide potentially interacts with GLP-1 receptors in the pancreas, which may stimulate insulin secretion from pancreatic beta cells and reduce glucagon production from alpha cells in a glucose-dependent manner. The GLP-1 receptor, a member of the class B G protein-coupled receptor family, is thought to primarily engage the cAMP-PKA signaling pathway in the pancreas. The interaction between GLP-1 and its receptor is believed to activate adenylate cyclase (AC), which converts ATP to cyclic adenosine monophosphate (cAMP), potentially increasing cAMP levels. This elevation in cAMP might activate protein kinase A (PKA) and the guanine nucleotide exchange factor RAPGEF4 (also known as EPAC2). The activated PKA may close ATP-sensitive K+ channels and depolarize the cell membrane, possibly activating voltage-dependent Ca2+ channels, leading to Ca2+ influx and the generation of action potentials. Furthermore, PKA might facilitate the release of Ca2+ by activating inositol trisphosphate (IP3). The activated EPAC2 may also activate Ras-related protein 1 and phospholipase C, possibly engaging the IP3 and diacylglycerol (DAG) pathways to further enhance Ca2+ release. Collectively, these pathways may increase intracellular Ca2+ levels, potentially boosting mitochondrial ATP synthesis and promoting insulin secretion via exocytosis.^[7]

Similar to its effects on GIP receptors, Retatrutide is suggested to influence neurons in the hypothalamic arcuate nucleus, involved in the regulation of appetite and hunger, possibly through GLP-1 receptors. These neurons express neuropeptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). It is theorized that direct activation of GLP-1 receptors on POMC/CART neurons might induce satiety and indirectly inhibit the release of hunger-stimulating peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP). Research also indicates that activation of GLP-1 receptors by agonists like Retatrutide may maintain elevated levels of free leptin and peptide YY3-36 (PYY3-36) during the reduction of weight.^[8]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. Folli F, Finzi G, Manfrini R, Galli A, Casiraghi F, Centofanti L, Berra C, Fiorina P, Davalli A, La Rosa S, Perego C, Higgins PB. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am J Physiol Endocrinol Metab. 2023 Nov 1;325(5):E595-E609. doi: 10.1152/ajpendo.00236.2023. Epub 2023 Sep 20. PMID: 37729025; PMCID: PMC10874655. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10874655/
2. Jakubowska A, Roux CWL, Viljoen A. The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor – An Update. Endocrinol Metab (Seoul). 2024 Feb;39(1):12-22. doi: 10.3803/EnM.2024.1942. Epub 2024 Feb 14. PMID: 38356208; PMCID: PMC10901658. https://pubmed.ncbi.nlm.nih.gov/38356208/
3. Doggrell SA. Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin Investig Drugs. 2023 May;32(5):355-359. doi: 10.1080/13543784.2023.2206560. Epub 2023 Apr 24. PMID: 37086147. https://pubmed.ncbi.nlm.nih.gov/37086147/
4. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023 Aug 12;402(10401):529-544. doi: 10.1016/S0140-6736(23)01053-X Epub 2023 Jun 26. PMID: 37385280. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01053-X/abstract
5. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023 Aug 10;389(6):514-526. doi: 10.1056/NEJMoa2301972. Epub 2023 Jun 26. PMID: 37366315. https://pubmed.ncbi.nlm.nih.gov/37366315/
6. Samms RJ, Sloop KW, Gribble FM, Reimann F, Adriaenssens AE. GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders. Diabetes. 2021 Sep;70(9):1938-1944. doi: 10.2337/dbi21-0002. Epub 2021 Jun 27. PMID: 34176786; PMCID: PMC8576420. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576420/
7. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne). 2021 Aug 23;12:721135. doi: 10.3389/fendo.2021.721135. PMID: 34497589; PMCID: PMC8419463. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419463/
8. Ard J, Fitch A, Fruh S, Herman L. Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists. Adv Ther. 2021 Jun;38(6):2821-2839. doi: 10.1007/s12325-021-01710-0. Epub 2021 May 11. PMID: 33977495; PMCID: PMC8189979. https://pubmed.ncbi.nlm.nih.gov/33977495/