Benefits and Side-Effects of Adipotide Peptides (FTPP)

by | Dec 15, 2022 | Research

 
Adipotide peptide is a synthetic peptidomimetic and an experimental proapoptotic drug known as FTPP (Fat-Targeted Proapoptotic Peptide). Peptidomimetics are synthetic molecules that mimic a natural protein’s structural domain. Adipotide binds to the protein receptor prohibitin, which is why it also bears the name Prohibitin-targeting peptide 1 (Prohibitin-TP01). By doing so, it has proapoptotic effects on adipose tissue, meaning that it causes cell death in white fat cells.

Animal studies show that by inducing targeted apoptosis, Adipotide peptide can cause dramatic fat loss, weight reduction, and improvement in several metabolic parameters.

It is important to note that this experimental proapoptotic drug has only been successfully tested in animals. The safety and effectiveness of its future use in humans have yet to be thoroughly studied and researched.

How Does Adipotide Peptide Work?

Adipotide peptide works by binding to the receptors for 2 specific proteins, ANXA2 (annexin A2) and prohibitin. Either of these receptors is expressed in various cells, but immunohistochemical analysis shows that they form specific ANXA2-prohibitin receptor systems in white fat tissue.[1]

Research reveals that these receptors play a role in regulating fatty acid transport in white adipose tissues.[2] Inhibiting the ANXA2 protein leads to hypertrophy of white adipose cells due to reduced uptake of fatty acids.

On the other hand, prohibitin is a multifunctional membrane-associated protein that is thought to regulate cell survival and growth. It can trigger apoptosis by shuttling from the cell’s membrane to its nucleus.

Adipotide peptide has a unique structure consisting of the amino-acid sequence GKGGRAKDC-GG-D(KLAKLAK)2. The 9 amino acid sequence CKGGRAKDC has a specific affinity to the ANXA2-prohibitin receptor system found in the blood vessels supporting white adipose cells.[3] At the same time, (KLAKLAK)2 disrupts mitochondrial membranes upon receptor-mediated cell internalization and causes programmed cell death.

As Adipotide peptide binds to prohibitin in white adipose vasculature, it triggers apoptosis and results in the ablation of white fat cells. 

According to research, Adipotide peptide and other similar peptidomimetics may effectively reduce subcutaneous and visceral fat and even target intra-organ fat, such as in fatty liver diseases.[4]

 

Applications of Adipotide Peptide in Obesity

Adipotide peptide may hold therapeutic potential for two major groups of patients – those with obesity (and obesity related-diseases) and those suffering from certain types of cancers.

Regarding its metabolic effects and the potential to induce fat loss, the peptidomimetic has been tested in mice, rats, and rhesus monkeys. In obese rats, 28 days of Adipotide peptide therapy led to a 30% reduction in body weight.[5] The medication also significantly suppressed their appetite, even though the leptin levels of the animals plummeted. Furthermore, the energy expenditure of the animals was not affected.

In another study, the researchers revealed that Adipotide peptide led to metabolic improvements as soon as the 3rd day of therapy, even before there was a noticeable reduction in the body weight of the tested mice. Kim et al. concluded that Adipotide “rapidly and potently improved the glucose tolerance of obese mice in a weight- and food intake-independent manner.”[6] The peptidomimetic significantly reduced triglyceride and insulin levels as well.

In obese rhesus monkeys, Adipotide peptide therapy caused white adipose tissue blood vessels to undergo targeted apoptosis.[7] As a result, the tested animals lost weight and improved their insulin sensitivity within the first month of therapy. A significant decrease in white adipose tissue was verified by dual-energy x-ray absorptiometry and magnetic resonance imaging.

 

Applications of Adipotide Peptide in Prostate Cancer

Apart from the benefits of Adipotide peptide in obesity, the destruction of white fat may also have positive consequences for men with prostate cancer. This is because a high level of white fat has been implicated as a critical contributing factor in poor prostate cancer outcomes.[8]

As a result, the FDA approved the first human trial involving Adipotide peptide therapy in prostate cancer patients. It evaluated the effect of a single cycle of Adipotide peptide in patients with castrate-resistant prostate cancer and no standard treatment options.

According to researchers, multiple patients successfully completed the entire study dosing cycle, but unfortunately, the trial was terminated before completion per the principal investigator’s request.[9, 10] Further research in human subjects is ongoing.

 

Are There Any Risks Associated with Adipotide Peptide Use?

Because Adipotide peptide has a peptide structure, its administration would require daily injections, which are associated with typical side effects related to the injection site. Examples of such adverse effects include redness, swelling, bleeding, and pain at the injection site.

In addition, some specific side effects are reported in the Adipotide peptide trials with test animals. In the experiment with rhesus monkeys, prolonged Adipotide peptide administration led to altered tubular function and renal injury.[7]

These adverse effects were reported to be relatively mild, predictable, dose-dependent, and reversible within 4 weeks of discontinuing the therapy. 

The researchers also reported that there was decreased serum phosphorus and potassium throughout the dosage interval, mild to moderate proteinuria, mild to notable glucosuria, and a modest to mild increase in transitional/renal epithelial cells.

 

Conclusion

Adipotide peptide is a promising anti-obesity agent which warrants further research and clinical trials. It may prove to be a valuable therapeutic option for the short-term management of obesity, especially in cases where the patients must achieve quick weight loss.

What holds the most promise is the fact that Adipotide peptide targets both subcutaneous and visceral fat. Visceral obesity is one of the leading causes that contribute to systemic inflammation, hypercholesterolemia, insulin resistance, and more. These are all risk factors for cancer, heart disease, diabetes, and stroke.

By causing a dramatic reduction in visceral body fat and energy intake, Adipotide peptide may help lower the risk of these debilitating diseases amongst the obese population. 

Furthermore, it may help improve the outcome in male patients with prostate cancer who do not respond to other therapies. 

Hopefully, future studies will dig into the potential of this peptidomimetic and provide us with an additional tool for dealing with the pandemic of obesity and obesity-related diseases which plagues the modern world.

 

References


  1. Staquicini FI, Cardó-Vila M, Kolonin MG, Trepel M, Edwards JK, Nunes DN, Sergeeva A, Efstathiou E, Sun J, Almeida NF, Tu SM, Botz GH, Wallace MJ, O’Connell DJ, Krajewski S, Gershenwald JE, Molldrem JJ, Flamm AL, Koivunen E, Pentz RD, Dias-Neto E, Setubal JC, Cahill DJ, Troncoso P, Do KA, Logothetis CJ, Sidman RL, Pasqualini R, Arap W. Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18637-42. doi: 10.1073/pnas.1114503108. Epub 2011 Nov 2. PMID: 22049339; PMCID: PMC3219136.
  2. Salameh A, Daquinag AC, Staquicini DI, An Z, Hajjar KA, Pasqualini R, Arap W, Kolonin MG. Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight. 2016 Jul 7;1(10):e86351. doi: 10.1172/jci.insight.86351. PMID: 27468426; PMCID: PMC4959783.
  3. Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004 Jun;10(6):625-32. doi: 10.1038/nm1048. Epub 2004 May 9. PMID: 15133506.
  4. Hossen N, Kajimoto K, Akita H, Hyodo M, Harashima H. A comparative study between nanoparticle-targeted therapeutics and bioconjugates as obesity medication. J Control Release. 2013 Oct 28;171(2):104-12. doi: 10.1016/j.jconrel.2013.07.013. Epub 2013 Jul 18. PMID: 23871959.
  5. Kim DH, Woods SC, Seeley RJ. Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight. Diabetes. 2010 Apr;59(4):907-15. doi: 10.2337/db09-1141. Epub 2010 Jan 26. PMID: 20103704; PMCID: PMC2844838.
  6. Kim DH, Sartor MA, Bain JR, Sandoval D, Stevens RD, Medvedovic M, Newgard CB, Woods SC, Seeley RJ. Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium. Diabetes. 2012 Sep;61(9):2299-310. doi: 10.2337/db11-1579. Epub 2012 Jun 25. PMID: 22733798; PMCID: PMC3425411.
  7. Barnhart KF, Christianson DR, Hanley PW, Driessen WH, Bernacky BJ, Baze WB, Wen S, Tian M, Ma J, Kolonin MG, Saha PK, Do KA, Hulvat JF, Gelovani JG, Chan L, Arap W, Pasqualini R. A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys. Sci Transl Med. 2011 Nov 9;3(108):108ra112. doi: 10.1126/scitranslmed.3002621. PMID: 22072637; PMCID: PMC3666164.
  8. Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol. 2013 May;63(5):800-9. doi: 10.1016/j.eururo.2012.11.013. Epub 2012 Nov 15. PMID: 23219374; PMCID: PMC3597763.
  9. Smith, T. L., Sidman, R. L., Arap, W., & Pasqualini, R. (2022). Targeting vascular zip codes: from combinatorial selection to drug prototypes. In The Vasculome (pp. 393-401). Academic Press.
  10. ClinicalTrials.gov [Internet]. National Library of Medicine (US). 2010 Dec 17 – . Identifier NCT01262664, A First-in-Man, Phase I Evaluation of A Single Cycle of Prohibitin Targeting Peptide 1 in Patients With Metastatic Prostate Cancer and Obesity; 2019 Jan 4; http://clinicaltrials.gov/ct2/show/NCT01262664

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