Tesamorelin Peptide: Potential Influence on the Hypothalamic–Pituitary–Somatotropic Axis

Tesamorelin is a research peptide that mimics the structure and functions of the endogenous hormone called growth hormone-releasing hormone (GHRH). Researchers suggest that GHRH is endogenously produced by the hypothalamus to stimulate the release of growth hormone (GH) by the somatotroph cells in the anterior pituitary gland. Similarly, Tesamorelin peptide appears to activate the same receptors as the GHRH (called GHRH receptors) and stimulate the pituitary cells to synthesize GH. This analogous potential is achieved thanks to the apparent similarities in the structure of GHRH and Tesamorelin. Both peptides constitute 44 amino acids, with the only difference being the addition of a trans-3-hexenoic acid to Tesamorelin. This addition is thought to increase the potential affinity of the peptide towards the GHRH receptors, and also increase its stability against degrading agents to increase its timeframe for activating the receptors.⁽¹⁾ Following Tesamorelin exposure, the somatotroph pituitary cells typically initiate increased GH synthesis within 30-60 minutes.⁽²⁾

 

Latest Research on Tesamorelin

Fig 1 – Tesamorelin Chemical Structure

Tesamorelin Peptide and Pituitary Cells

Tesamorelin peptide potentially interacts with pituitary gland cells by binding to GHRH receptors on their surface, initiating a sequence of molecular events. Researchers propose that this binding causes structural alterations in the GHRH receptors such as a significant conformational change involving transmembrane helix 6 (TM6), opening the intracellular face for G protein coupling.^(3,4) Consequently this may activate the enzyme adenylate cyclase, which converts ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate). These increased cAMP levels activate protein kinase A (PKA), leading to protein phosphorylation and amplification of GHRH receptor signaling initiated by Tesamorelin, which in turn stimulates the synthesis and secretion of growth hormone from somatotrophs in the anterior pituitary gland. Research indicates that Tesamorelin induces up to a 69% increase in overall GH production by somatotroph cells, as measured by the 12-hour area under the curve (AUC), which quantifies the total hormone concentration over 12 hours. Additionally, the researchers reported that “The overall increase in GH secretion was comprised of both increased basal GH secretion (…) and increased average pulse area”. Specifically, there was approximately a 55% increase in the average pulse area of GH, reflecting the amount of hormone released during each pulse. Furthermore, levels of insulin-like growth factor 1 (IGF-1) surged by approximately 122%.⁽⁵⁾ IGF-1 is considered the main anabolic mediator of GH, which is produced under its influence in peripheral tissues and may stimulate cell proliferation and increase protein synthesis in various cell lines – skin cells, muscle cells, bone cells, tendon cells, and more.

Tesamorelin Peptide and Visceral Fat Cells

Tesamorelin peptide is posited to interact with fat cells indirectly, via the elevated levels of GH which are apparently stimulated by the peptide. This Tesamorelin-induced GH elevation may upregulate the action of the hormone on fat cells, which involves interaction with key enzymes regulating fat storage and breakdown in these cells. Namely, in vitro trials suggest that GH, including Tesamorelin-induced GH, may exert lipolytic effects on adipocytes by activating hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL).⁽⁶⁾ These enzymes stimulate triglyceride hydrolysis and the release of free fatty acids from fat cells. Specifically, GH may stimulate lipolysis by increasing cAMP levels, which activate PKA. PKA phosphorylates HSL, enhancing its activity and leading to the breakdown of triglycerides into free fatty acids and glycerol.

Researchers also posit that the activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by Tesamorelin-induced GH may lead to the transcription of genes involved in lipid mobilization.⁽⁷⁾ They have concluded that “GH impacts adipose tissue in a depot-specific manner and influences other features of adipose tissue (for example, senescence, adipocyte subpopulations and fibrosis), all of which could influence lipolysis.” Indeed, adipose cells are heterogeneous, with visceral and subcutaneous fat cells exhibiting distinct metabolic profiles. Growth hormone, including Tesamorelin peptide-induced GH, appears to affect the tissue in a depot-specific manner, preferentially targeting visceral adipocytes. These are fat cells that are typically derived from the visceral fat building up in excess around the abdomen and abdominal organs. The specificity of GH may be attributed to the higher expression levels of GH receptors in visceral fat cells compared to subcutaneous fat cells. The enhanced sensitivity of visceral fat cells to GH is posited to lead to increased lipolysis and fatty acid oxidation in these cells.⁽⁸⁾ Clinical data has suggested that Tesamorelin-induced GH may lead to a mean -18% reduction in visceral fat levels.

By reducing visceral fat, Tesamorelin-induced GH may also decrease the flux of free fatty acids to the liver. Since excess free fatty acids are posited as a major potential contributor to fatty liver, their reduction is expected to help lower liver fat levels. Increased lipolysis by the action of GH within the liver cells may also directly decrease the accumulation of triglycerides in hepatocytes, thereby reducing hepatic fat fraction.⁽⁹⁾ Indeed, interventional research suggests that Tesamorelin might lower absolute hepatic fat levels by 4.7% which represents a relative decrease in liver fat by 37%, compared to no relative or absolute changes observed during placebo experimentation.⁽¹⁰⁾ Moreover, the peptide has been suggested to be almost 4 times more effective than placebo in slowing down liver cell fibrosis, which is the process of replacement of liver cells with scar tissue. This also results in reduced release of liver enzymes from liver cells, such as alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) which are important markers for liver cell damage.

Tesamorelin Peptide and Cholesterol Metabolism

The reduction of the fat content in visceral fat cells is expected to ultimately reduce the release of free fatty acids, which are then less likely to be converted into cholesterol by other cells such as hepatocytes. Moreover, elevated GH synthesis, such as due to Tesamorelin-induced GH peaks, may upregulate the expression of LDL receptors like those found in liver cells, which are responsible for picking up and metabolizing LDL cholesterol.⁽¹¹⁾  Reduced production and increased uptake of LDL cholesterol are expected to lower its levels in the extracellular environment.

Tesamorelin Peptide and Muscle Cells Metabolism

As noted, By influencing the hypothalamic-pituitary–somatotropic axis, Tesamorelin peptide is expected to elevate GH production in pituitary somatotroph cells, which in turn is believed to upregulate the synthesis of IGF-1 in peripheral cells such as liver and muscle cells. In vitro experimentation suggests that Tesamorelin-induced GH synthesis can elevate intramuscular IGF-1 levels, consequently improving mitochondrial function and muscle energy metabolism.⁽¹²⁾ Such actions are expected to potentially improve the function of muscle cells, including parameters such as strength, size and endurance.

Within muscle cells, IGF-1 may bind to its specific receptor, IGF-1R, triggering a cascade of intracellular signaling events. This binding activates phosphoinositide 3-kinase (PI3K), which in turn phosphorylates and activates the protein kinase Akt. Once activated, Akt stimulates the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. mTOR is considered to play a crucial role in enhancing the production of cellular proteins by promoting the formation of new ribosomes and increasing ribosomal activity. This leads to the synthesis of new proteins that contribute to muscle cell growth, function, strength, and size.⁽¹³⁾ In addition to its role in promoting protein synthesis, IGF-1 may help reduce the breakdown of existing muscle cell proteins. IGF-1 signaling is posited to suppress the expression of muscle-specific E3 ubiquitin ligases, such as atrogin-1 and muscle ring finger protein-1 (MuRF1), which are involved in targeting proteins for degradation. By downregulating these ligases, IGF-1 may decrease muscle protein degradation and support muscle cell preservation.⁽¹⁴⁾ Another key action of Tesamorelin-induced increase in the expression of IGF-1 is its potential to increase the translocation of glucose transporter type 4 (GLUT4) to the muscle cell membrane, facilitating glucose uptake. The increased availability of glucose inside muscle cells may not only support immediate energy demands but also enhance glycogen synthesis, potentially providing a reserve energy source within the muscle cells. This may contribute to the overall metabolic support for muscle cell function and recovery.⁽¹⁵⁾

Tesamorelin Peptide and Nerve Cell Signaling

There is emerging evidence that Tesamorelin peptide may influence levels of neurotransmitters such as γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG) in the central nervous system.⁽¹⁶⁾ Tesamorelin possibly increases GABA concentrations across various nerve cell populations, including those in the dorsolateral frontal cortex, posterior cingulate, and posterior parietal areas, based on research using proton magnetic resonance spectroscopy (MRS). This increase in GABA, which is considered the main inhibitory neurotransmitter, might suggest that Tesamorelin peptide could play a role in modulating inhibitory signaling pathways within the central nervous system. Additionally, Tesamorelin may elevate NAAG levels, particularly in the dorsolateral frontal cortex. NAAG is another neurotransmitter with inhibitory properties, often linked to the modulation of glutamate activity through its action on metabotropic glutamate receptors. The increase in NAAG suggests that Tesamorelin could potentially affect broader inhibitory networks in the central nervous system. However, this action appears localized, as NAAG increases were not observed uniformly across the nerve cell populations in all regions. While the precise mechanisms by which Tesamorelin may modulate these neurotransmitters remain unclear, the observed changes in GABA and NAAG could be indicative of their potential to alter the inhibitory-excitatory balance in nerve cell degeneration and aging. The research also points to possible indirect effects via interactions with IGF-1, as changes in GABA and NAAG levels might correlate with IGF-1, further complicating the interpretation of how these neurochemical shifts occur.

 
NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Ferdinandi, E. S., Brazeau, P., High, K., Procter, B., Fennell, S., & Dubreuil, P. (2007). Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic & clinical pharmacology & toxicology, 100(1), 49–58. https://doi.org/10.1111/j.1742-7843.2007.00008.x
2. González-Sales, M., Barrière, O., Tremblay, P. O., Nekka, F., Mamputu, J. C., Boudreault, S., & Tanguay, M. (2015). Population pharmacokinetic and pharmacodynamic analysis of Tesamorelin in HIV-infected patients and healthy subjects. Journal of pharmacokinetics and pharmacodynamics, 42(3), 287–299. https://doi.org/10.1007/s10928-015-9416-2
3. Spooner, L. M., & Olin, J. L. (2012). Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. The Annals of pharmacotherapy, 46(2), 240–247. https://doi.org/10.1345/aph.1Q629
4. Zhou, F., Zhang, H., Cong, Z., Zhao, L. H., Zhou, Q., Mao, C., Cheng, X., Shen, D. D., Cai, X., Ma, C., Wang, Y., Dai, A., Zhou, Y., Sun, W., Zhao, F., Zhao, S., Jiang, H., Jiang, Y., Yang, D., Eric Xu, H., … Wang, M. W. (2020). Structural basis for activation of the growth hormone-releasing hormone receptor. Nature communications, 11(1),
5. Stanley TL, Chen CY, Branch KL, Makimura H, Grinspoon SK. Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab. 2011 Jan;96(1):150-8. doi: 10.1210/jc.2010-1587. Epub 2010 Oct 13. PMID: 20943777; PMCID: PMC3038486.
6. Kopchick, J. J., Berryman, D. E., Puri, V., Lee, K. Y., & Jorgensen, J. O. L. (2020). The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nature reviews. Endocrinology, 16(3), 135–146. https://doi.org/10.1038/s41574-019-0280-9
7. Dehkhoda, F., Lee, C. M. M., Medina, J., & Brooks, A. J. (2018). The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Frontiers in endocrinology, 9, 35. https://doi.org/10.3389/fendo.2018.00035
8. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol. 2020 Mar;16(3):135-146. doi: 10.1038/s41574-019-0280-9. Epub 2019 Nov 28. PMID: 31780780; PMCID: PMC7180987.
9. Falutz, J., Potvin, D., Mamputu, J. C., Assaad, H., Zoltowska, M., Michaud, S. E., Berger, D., Somero, M., Moyle, G., Brown, S., Martorell, C., Turner, R., & Grinspoon, S. (2010). Effects of Tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. Journal of acquired immune deficiency syndromes (1999), 53(3), 311–322. https://doi.org/10.1097/QAI.0b013e3181cbdaff
10. Stanley, T. L., Fourman, L. T., Feldpausch, M. N., Purdy, J., Zheng, I., Pan, C. S., Aepfelbacher, J., Buckless, C., Tsao, A., Kellogg, A., Branch, K., Lee, H., Liu, C. Y., Corey, K. E., Chung, R. T., Torriani, M., Kleiner, D. E., Hadigan, C. M., & Grinspoon, S. K. (2019). Effects of Tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. The lancet. HIV, 6(12), e821–e830.
11. Machado, M. O., Hirata, R. D., Hirata, M. H., Hirszel, P., Sellitti, D. F., & Doi, S. Q. (2003). Growth hormone increases low-density lipoprotein receptor and HMG-CoA reductase mRNA expression in mesangial cells. Nephron. Experimental nephrology, 93(4), e134–e140. https://doi.org/10.1159/000070237
12. Makimura, H., Murphy, C. A., Feldpausch, M. N., & Grinspoon, S. K. (2014). The effects of Tesamorelin on phosphocreatine recovery in obese subjects with reduced GH. The Journal of clinical endocrinology and metabolism, 99(1), 338–343. https://doi.org/10.1210/jc.2013-3436
13. Yoshida, T., & Delafontaine, P. (2020). Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells, 9(9), 1970. https://doi.org/10.3390/cells9091970
14. Sacheck, J. M., Ohtsuka, A., McLary, S. C., & Goldberg, A. L. (2004). IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. American journal of physiology. Endocrinology and metabolism, 287(4), E591–E601. https://doi.org/10.1152/ajpendo.00073.2004
15. Muhič, M., Vardjan, N., Chowdhury, H. H., Zorec, R., & Kreft, M. (2015). Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes. The Journal of biological chemistry, 290(17), 11167–11176. https://doi.org/10.1074/jbc.M114.629063
16. Friedman, S. D., Baker, L. D., Borson, S., Jensen, J. E., Barsness, S. M., Craft, S., Merriam, G. R., Otto, R. K., Novotny, E. J., & Vitiello, M. V. (2013). Growth hormone-releasing hormone effects on brain γ-aminobutyric acid levels in mild cognitive impairment and healthy aging. JAMA neurology, 70(7), 883–890. https://doi.org/10.1001/jamaneurol.2013.1425