The Metabolic Role of Tetradecylthioacetic Acid (TTA)
By the VPX R & D team
(Preamble: at VPX, we use only the most cutting edge, highly researched ingredients. Tetradecylthioacetic acid (aka TTA or MTTA) is an example of how the R & D team at VPX always brings you the very best, the superlative, and the most efficacious products).
Tetradecylthioacetic acid (TTA) is a structurally modified form of fatty acid known as a 3-thia fatty acid. Thia fatty acids are saturated fatty acids which are modified by inserting a sulfur atom at a specific position in the carbon backbone. In the case of TTA, the sulfur atom is inserted in the 3-position of the carbon backbone, hence the classification as a "3"-thia fatty acid. Over the past several years, various beneficial properties have been attributed to the use of TTA (most often using animal models and/or in vitro systems [i.e., testing within an artificial environment outside of the body]). For a summary of such effects, readers are referred to the excellent review by Berge and coworkers (2002).
While the following listing may not be comprehensive, the novel fatty acid TTA has been reported in the literature to have effects on:
- Improving the plasma profile from atherogenic to cardio protective (Berge et al., 1999)
- Stimulating immune function (Aukrust et al., 2003)
- Possessing anti-inflammatory properties (Aukrust et al., 2003; Bivol et al., 2008; Dyroy et al., 2005)
- Decreasing reactive oxygen species (Bivol et al., 2008; Muna et al., 1997; 2000; 2002)
- Maintaining nitric oxide production (Bivol et al., 2008)
- Inhibiting cancer cell infiltration (Iversen et al., 2006) and growth (Jensen et al., 2007)
- Decreasing smooth muscle cell proliferation (Kuiper et al., 2001)
- Inducing an increase in mitochondrial growth (Totland et al., 2000)
- Increasing fatty acid oxidation (Berge and Hvattum, 1994; Skrede and Bremer, 1993)
- Improving insulin sensitivity (Madsen et al., 2002)
Although the above listing of the effects of TTA is impressive, the latter effects on mitochondrial growth, fatty acid oxidation, and insulin sensitivity may be of most interest to bodybuilders and fitness enthusiasts attempting to decrease body fat mass. It has been reported over the past 15 years or so that structurally modified fatty acids exhibit an enhanced effect in controlling lipid metabolism, as compared to their biologically formed counterparts. As such, these modified fatty acids may play a role in enhancing both health and body fat loss. The following text will discuss the benefits of TTA in relation to these findings, with a particular emphasis on mitochondrial growth and fatty acid oxidation.
Mitochondrial Growth and TTA
The oxidation of fatty acids occurs in the mitochondria of the cell through a process known as beta oxidation. The entire process of fatty acid metabolism involves multiple steps in which fats are first mobilized from storage sites and ultimately "burned" for energy. Although TTA itself is not processed through beta oxidation, it does stimulate the beta oxidation of other fatty acids (Berge and Hvattum, 1994). It is important to note that in addition to stimulating the oxidation of other fatty acids, TTA has been shown to result in an increase in actual mitochondria, as well as an increase in gene expression of some key enzymes involved in fatty acid oxidation (Totland et al., 2000). This is important as the amount of mitochondria and enzymes involved in fatty acid metabolism may be associated with the overall rate of lipid oxidation.
In previous work mitochondrial growth has been shown to be induced in both type I (slow twitch) and type II (fast twitch) skeletal muscle fibers, as well as in the diaphragm (Totland et al., 2000). Moreover, TTA increased the gene expression of carnitine palmitoyltranserferase II in the diaphragm, an enzyme crucial for the transport of activated fatty acids inside the mitochondria to undergo beta oxidation. Taken together, these effects of TTA on mitochondrial growth and gene expression may prove beneficial to the end result of increased fat oxidation. However, it should be noted that similar to the majority of studies using TTA as a therapeutic agent, the work of Totland et al. (2000) used rats that were fed these modified fatty acids. Replicated work in human subjects administered the same therapeutic dosages is necessary before conclusions can be drawn in relation to the impact of TTA on fatty acid oxidation in human subjects.
Fatty Acid Oxidation and TTA
As mentioned above, although TTA itself is not oxidized through beta oxidation, it has been shown to stimulate the beta oxidation of other fatty acids (Berge and Hvattum, 1994) and is clearly involved in lipid transport and utilization (Berge et al., 2005). This suggests that TTA may promote greater fatty acid usage and hence, greater fat loss over time. This may be partly due to the observation that TTA increases the transport of fatty acids into the mitochondria to undergo beta oxidation, as well as enhancing the process of beta oxidation itself (Madsen et al., 1999), which appears most prevalent in the liver (Berge et al., 2005). Related to this, several studies have reported on the beneficial effects of TTA administration related to fatty acid oxidation.
Skrede and Bremer (1993) noted that a single morning dosage of TTA (100mg) in rats increased fatty acid oxidation in isolated liver cells to values 3x greater than control (non-TTA treated) within 6 hours. Other work supports the role of TTA in increasing fatty acid oxidation, in addition to an increase in the production of ketones, which can be used as a fuel source (Madsen et al., 2002). Related to these findings, TTA has been shown to impart a significant effect on lowering blood lipids (total and LDL cholesterol), with a noted 56% reduction in VLDL-triacylglycerol (Asiedu et al., 1996). Similar effects have been noted in human subjects with HIV, in addition to a decrease in inflammation with TTA supplementation (Fredriksen et al., 2004). The effect on blood lipids may be partly related to the increase in fatty acid oxidation coupled with an increased gene expression for LDL receptors, which function in the removal of LDL cholesterol from circulation (Fredriksen et al., 2004). Such findings may have significant implications related to cardiovascular health.
Aside from the increase in fatty acid oxidation and the improvement in the blood lipid profile, TTA has been reported to prevent adiposity (accumulation of excess fat tissue) and to prevent insulin resistance, when rats were fed a high fat diet (Madsen et al., 2002). In this interesting study, it was noted that TTA treatment completely prevented the dietary-induced insulin resistance that is typically observed when animals consume a high fat diet, as well as prevented the accumulation of excess fat. This is an important finding, as insulin resistance is strongly associated with impaired glucose tolerance, often leading to obesity and the development of type II diabetes. The potential mechanism of action for these effects involves transcription factors known as peroxisome proliferators-activated receptors (PPAR), of which three distinct subtypes have been identified (alpha, gamma, delta/beta). The activation of these receptors by TTA (in particular PPARα) appears to be associated with the positive effects on gene activation related to enzymes involved in fatty acid transport and oxidation (Larsen et al., 2005).
Methylation is a common term used in chemistry and biochemistry to denote the attachment or substitution of a methyl group onto various molecules. A few studies have reported that the methylated version of TTA may have more potent metabolic properties than the unmethylated fatty acid. This appears specifically related to the increased activation of PPARα (Larsen et al., 2005). The increased activation of PPARα has been associated with increased gene expression of acyl-CoA oxidase and liver fatty acid binding protein, both of which are involved in fatty acid metabolism. Hence, methylated versions of TTA may prove most beneficial in relation to fatty acid oxidation, as well as provide further metabolic effects as denoted in the text above. Additional study is necessary to confirm these initial findings.
TTA in Human Subjects
As noted in the Introduction of this article, most studies focused on TTA have used animal models, as opposed to humans, while many others have used in vitro systems. Hence, while data with TTA are indeed interesting, it is imperative that well-designed human studies are conducted to replicate the above findings prior to firm conclusions being drawn regarding the metabolic effects of TTA in human subjects. That being said, at least one human study has been conducted recently using TTA (Fredriksen et al., 2004). In this work, ten HIV-infected subjects with hyperlipidemia were put on a cholesterol lowering diet for an eight week period. During the final 4 weeks of the study all subjects received TTA at a dosage of 1000mg per day, while continuing on the cholesterol lowering diet. It was noted that TTA promoted a significant reduction in total and LDL cholesterol, in addition to a reduction in the inflammatory cytokine TNFα. While these findings should be considered as pilot data, with no "true" control group, they are indeed interesting and may provide grounds for further work to investigate the metabolic effects of TTA in human subjects.
As presented, TTA has multiple potential benefits which may apply to human subjects. These include, but are certainly not limited to, enhanced fatty acid transport and oxidation for use as an energy source. These findings may be of particular interest to bodybuilders and fitness enthusiasts who have the goal of increased fat utilization both at rest and in the context of an acute exercise bout. Additional studies are needed to determine the impact of this modified fatty acid related to fat utilization and subsequent body fat loss in human subjects participating in programs of structured exercise.
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