Adipotide (FTPP) Actions on Fat Cell Size and Metabolism

Adipotide (FTPP) is considered to be a chimeric peptide (GKGGRAKDC-GG-D(KLAKLAK)₂) engineered to target endothelial cells from white-adipose vasculature and induce their apoptosis. As a chimeric peptide, it is believed to consist of two functional parts. The first of these parts is a short cyclic sequence of amino acids – CKGGRAKDC. This targeting motif may function as a structural mimic of annexin A2 (ANXA2), a protein that has been implicated in membrane organization and protein–protein interactions within endothelial cells. Thus, CKGGRAKDC is thought to mediate the specificity to endothelial cells found in white-adipose vasculature by binding to a membrane protein called prohibitin.

The second part of the peptide, linked via a short Gly-Gly bridge, appears to be the proapoptotic sequence D(KLAKLAK)₂. This fragment is posited to be amphipathic, which may allow it to interact with the membrane. Once inside a cell, it may have the capacity to disrupt mitochondrial membranes, thereby triggering the process of apoptosis. The peptide was pioneered by the research team of Kolonin et al., and their research suggests that the peptide may produce a reduction in white fat cells, decreased ectopic fat accumulation, and increased lipid turnover.⁽¹⁾

Currently, Adipotide (FTPP) is under active laboratory research to clarify the mechanistic basis of prohibitin recognition, assess the selectivity of the CKGGRAKDC motif for white adipose depots versus other vascular beds, and evaluate the metabolic consequences of adipose vascular ablation in controlled systems.

 

Research

Adipotide (FTPP) Support for Fatty Acid Flow

Adipotide (FTPP) has been described as a prohibitin-targeting peptide through its CKGGRAKDC motif, but emerging studies suggest that its activity might also be relevant to fatty acid handling pathways. Research by Salameh et al. suggests that “biochemical interaction between ANX2 and PHB regulates CD36-mediated fatty acid transport in WAT” and thus facilitates fatty acid uptake and transfer from endothelial cells into white-adipose tissue cells.⁽²⁾

Because Adipotide (FTPP) appears to engage prohibitin, this interaction might interact with the stability or organization of the prohibitin/ANXA2/CD36 complex. If so, disruption of this assembly might reduce the efficiency of CD36-mediated fatty acid transport. Laboratory studies on Adipotide (FTPP) by Salameh et al. suggest the peptide may result in smaller adipocytes, fewer adipogenic/angiogenic clusters, and reduced immune cell content around adipose cells. Exposure to the peptide in laboratory settings also coincided with less ectopic lipids observed in mammalian models, without detectable toxicity towards liver cells in the reported conditions.⁽³⁾

Adipotide (FTPP) Actions on Fat Cells with Different Origins

Research studies by Barnhart et al. suggest that Adipotide (FTPP) may target cells associated with different fat depots, including both visceral fat cells and peripheral fat cells.⁽⁴⁾ Because the same white-fat vasculature supplies both depots, the targeting mechanism apparently allows the peptide to act across cells with different origins rather than being restricted to only one. Imaging data indicate that reductions in fat cell volume occur in both visceral and subcutaneous tissues, which may point to a shared vulnerability of their endothelial networks.

According to the researchers, there was about a 38.7% reduction in adipose cell volume following experimentation with the peptide. This is also independently observed by other researchers, such as Kim et al., who also suggest that the peptide may specifically target enlarged adipocytes, while exerting a lesser action on smaller cells.⁽⁵⁾ By reducing the volume of these fat cells, the peptide may indirectly support insulin metabolism. Apparently, the researchers observed “a modest reduction in serum-free fatty acids and an increase in insulin resistance.”

This action is possibly related to a decrease in signals released from enlarged adipocytes, as well as changes in nutrient handling once the vascular supply is altered. Specifically targeting visceral fat cells may contribute to better insulin sensitivity. Unfortunately, the peptide may not be entirely selective, as the data also suggest that kidney cells, particularly those in the tubular structures, may also interact with it. This raises the possibility of off-target interactions, which were observed as mild and reversible changes in laboratory settings.

Adipotide (FTPP) and the Insulin Sensitivity of Fat Cells

A more recent experiment by Kim et al. suggests that the actions of Adipotide (FTPP) on the insulin metabolism in adipose cells may occur rapidly following experimentation, even before the shrinking of the fat cells.⁽⁶⁾ The researchers suggested that markers of glucose handling by the cells support almost immediately, with lower insulin exposure needed to manage it. Signals normally secreted by fat cells also appeared to shift, as the researchers observed an apparent resistin decline, a tendency for adiponectin to rise, and apparently more favorable lipid changes related to reduced release of triglycerides and specific free fatty acids.

At the molecular level, adipose tissue cells may have taken a course towards a reversal of patterns usually linked to high-fat expansion. Genes involved in mitochondrial function and branched-chain amino acid metabolism appeared to move toward a more balanced state. At the same time, acylcarnitine levels indicate a lower reliance on fatty acid and amino acid oxidation. Therefore, Kim et al. concluded that observations of “mitochondrial dysfunction, oxidative phosphorylation, and branched-chain amino acid degradation” related to the oversaturation of fat cells with lipids were amended by Adipotide (FTPP) exposure. These shifts suggest that metabolic flexibility occurs before the fat cells themselves have released all fats and shrunk, pointing to changes beyond fat cell mass.

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References:

1. 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.
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. 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.
4. 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 supportd insulin resistance in obese monkeys. Sci Transl Med. 2011 Nov 9;3(108):108ra112. doi: 10.Doi6/scitranslmed.3002621. PMID: 22072637; PMCID: PMC3666164.
5. Kim DH, Woods SC, Seeley RJ. Peptide is designed to elicit apoptosis in adipose tissue endothelium and reduce 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 enhancement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium. Diabetes. 2012 Sep;61(9):2299-310. Epub 2012 Jun 25. PMID: 22733798; PMCID: PMC3425411. https://doi.org/10.2337/db11-1579