Studies of Conjugated Linoleic Acid (CLA)

Studies of Conjugated Linoleic Acid (CLA)


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Conjugated linoleic acid (CLA) is found naturally in food, although the total CLA content varies. 1995 CLA is a modified isomer of linoleic acid that was introduced to the supplement market in late 1995 as one of the newer supplements available to enhance muscular development. Chemically, linoleic acid is an 18-carbon unsaturated fatty acid with two double bonds in positions 9 and 12, respectively. Both of these bonds lie in the cis configuration, thus giving it its own unique chemical name-c9, c12­octadecadienoic acid.

CLA differs only modestly in confirmation in that the two double bonds in CLA are in one of three positions along the carbon chain: 9 and 11, 10 and 12, or 11 and 13. These small changes not only give CLA a unique chemical name, but because of the varied position of the double bonds, CLA also can take two different geometric positions. Therefore, CLA can take a cis or trans configuration.

Although this may seem chemically insignificant, physiologically it is quite profound and gives CLA the chemical nomenclature of a conjugated diene that is a mixture of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. With a few exceptions, the c9, t11-isomer is the predominant form CLA is found especially in foods high in saturated fat such as meat and dairy products. In addition, meat from ruminants (animals with four-chambered stomachs) contains more CLA than meat from nonruminants.

Because foods typically high in CLA also contain high amounts of saturated fats, increasing CLA intake via food consumption may put individuals at risk for developing coronary artery disease. Nevertheless, there are intriguing data that demonstrate positive effects after CLA administration.

During processing, various factors may contribute to the formation of CLA. Factors that increase CLA food content include higher temperatures, the addition of whey protein concentrate or sodium caseinate, and the presence of a hydrogen donor such as butylated hydroxy toluene, propyl gallate, or ascorbic acid. Although some reports suggest that grilling ground beef may increase CLA content in beef fat by about four-fold, other studies suggest that cooking has no effect on CLA concentrations.

Owing to this unique molecular structure, CLA is believed to have unique mammalian tissue physiological effects compared with other fats. Scientists have theorized, from observations in various animal studies, that CLA enhances lean body mass, although the mechanism for action is unknown. Some scientists believe that CLA amplifies cell responsiveness to certain growth factors, hormones, and cellular messengers. It may also possess anticatabolic effects Therefore, CLA consumption by humans could theoretically increase muscular strength and lean body mass. Whether supplementation is advised is still a matter of debate.

Animal Studies

CLA has been suggested to also be anticarcinogenic. The incidence of various forms of cancer is high in the United States and other countries. Saturated fat has been correlated with the occurrence of cancer in several tissue sites Certain unsaturated fatty acids may affect carcinogenic factors. For example, linoleic acid has been implicated in the acceleration of mammary cancer development in rodents However, it is also clear that some fatty acids will inhibit carcinogenesis. In this regard, eicosapentaenoic acid and docosahexaenoic acid, which are representative of the w-3 polyunsaturated fatty acids found in fish oil, have long been purported to have anticarcinogenic effects. acid, CLA appears to have reproducible effects on various cancer indices.

To date, the specific sites of action include breast. colon kidney and skin tissue. The reason CLA has these effects may lie in how it is deposited in tissues. One interesting finding is that the c9, t11-isomer appears to be found in the phospholipid layer, whereas other CLA isomers appear in triglyerides. The reason why this relationship is important is not completely clear. However, the ingestion of CLA likely leads to an accumulation in triglyceride, which is stored as fat depot in adipocytes. Because CLA has an antioxidant potential and because adipocytes are a major constituent of the mammary gland, the increased concentration of CLA in triglyceride may help protect certain cells against oxidant stress.

Although the exact mechanism of action has yet to be confirmed, use of CLA as a therapeutic intervention shows promise. For example, Ip has shown that, although fish oil is a class of lipid that inhibits both chemically induced and transplantable tumors, the amount of fish oil needed to elicit this response usually exceeds 10% of total dietary fat However, as little as 0.1% CLA in the diet is sufficient to produce a significant reduction in mammary tumor yield.

Although CLA appears to play a role in the inhibition of carcinogenesis, it also appears to have insulin-sensitizing effects as well. In this regard, CLA activates PPAR alpha in the liver and shares functional similarities to ligands of PPAR gamma and thiazolidinediones, which are potent insulin sensitizers. Early evidence for the effect of CLA on insulin sensitivity was provided by Houseknecht et al. who reported that CLA was able to normalize impaired glucose tolerance and improve hyperinsulinemia in prediabetic rats.

Additionally, dietary CLA in this trial also appeared to increase steady-state levels of aP2 (activator protein 2) mRNA in adipose tissue, which is consistent with the actions of PPAR gamma. The authors of this study proposed that the insulin-sensitizing effects of CLA are caused, at least in part, by activation of PPAR gamma because increasing levels of CLA induced a dose­dependent transactivation (stimulation of transcription by a transcription factor binding to DNA and activating adjacent proteins) of PPAR gamma.

In vitro data on human erythrocytes have also been presented by Inouye et al These investigators suggest that glycation reactions and antioxidant activity are enhanced by elevated glucose concentrations. Because it is unclear whether the diabetic state, perse, also induces an increase in the generation of oxygen-derived free radicals, there is some evidence that glycation itself may induce the formation of oxygen-derived free radicals. In this regard, oxygen­derived free radicals could cause oxidative damage to endogenous molecules.

During this trial, investigators examined the relationship between the levels of lipid peoxidation and the levels of glycated hemoglobin Ale in the erythrocytes of both diabetic and healthy subjects. Lipid peroxidation was assessed in erythrocyte membrane lipids by monitoring peak height ratios of CLA, one of the products of lipid peroxidation, to linoleic acid. The peak height ratio of CLA to LA was used as a biomarker of lipid peroxidation and glycated hemoglobin Ale, an index of glycemic stress.

The results of this trial showed a significant increase in the ratios of CLA to LA in diabetic erythrocytes compared with that of control erythrocytes. In addition, ratios of CLA to LA were also significantly correlated with glycated hemoglobin Ale values. These findings attest to the antioxidant qualities of CLA and suggest that glycation via chronic hyperglycemia links lipid peroxidation in the erythrocytes of both diabetic and healthy subjects. (Hemoglobin Ale is the substance of red blood cells that carries oxygen to the cells and sometimes joins with glucose.)

Although it has been shown that CLA may have anticarcinogenic effects and the ability to modulate diabetic and immune system responses, less is certain about its effect on body mass. Animal studies have shown that CLA can increase lean body mass and decrease fat. Studies in animals also show that CLA improves feed efficiency, which means that animals given CLA gain weight without receiving more food. If validated in human studies, these results could have interesting applications in athletics as well as medicine.

Recent investigations have demonstrated that animals receiving a diet rich in CLA have a reduction in adipose tissue. One such study fed mice a diet of 5.5% corn oil or a CLA-supplemented diet consisting of 5.0% corn oil plus 0.5% CLA. Mice receiving the supplement exhibited 57% and 60% lower body fat and 5% and 14% increased lean body mass compared with controls.

Total carnitine palmitoyltransferase activity, an enzyme used in the oxidation of fatty acids, was increased in fat pad and skeletal muscle sites of the experimental animals. Cell culture experiments used adipocytes were also conducted and showed that CLA treatment significantly reduced heparin-releasable lipoprotein lipase activity (- 66%) as well as the intracellular concentrations of triglycerides (-8%) and glycerol (-15%). However, CLA significantly increased free glycerol in the culture medium compared with the control.

Researchers concluded that the effects of CLA on body composition appear to be a result in part of reduced fat deposition and increased lipolysis in adipocytes, along with enhanced fatty acid oxidation in myocytes and adipocytes. Another interesting observation was the increase in the percentage of whole body protein and carcass water in mice receiving CLA supplementation.

Unfortunately, because of the small sample size, it was not possible to conclude from these data alone that CLA induced a significant increase in protein accretion. However, these investigators also mention data combined from 10 other CLA studies, which indicate that CLA-fed mice do in fact exhibit increased whole body protein relative to control animals. Their findings have led to further research examining alterations in lean body mass induced by the supplementation of CLA.

Park et al recently published a two-part experiment. In the first part, 8-week-old mice were fed a control diet or a diet supplemented with 0.5% CLA. Results from each feeding showed parallel, but significantly distinct responses for both absolute and relative changes in body fat mass, which was decreased in the CLA-fed mice. In addition, relative alterations in whole body protein and whole body water were both increased in the experimental group. In the second part of the experiment, weanling mice were fed a control diet or a diet with added CLA (0.5% CLA) for 4 weeks. After 4 weeks, all mice were fed the control diet (no CLA).

The experimental group exhibited significantly reduced body fat and significantly enhanced whole body water relative to controls at the time of the shift in food composition. Time trends for the changes in relative body composition were described as the CLA-fed group exhibited significantly less body fat, but significantly more whole body protein, whole body water and whole body ash than controls. Tissue analyses of the animals revealed that the CLA isomer t-10, c-12 was cleared significantly faster than was the c-9, t-11 isomer. These findings confirm data showing that CLA given to mice can increase whole body protein and whole body water, and decrease fat mass. Changes in body composition were still visible 8 weeks after the cessation of supplementation. This indicates CLA can induce effects on muscle mass and adipose tissue for at least some time after the clearance of the compound.

Particularly interesting in these studies are the different effects of the various isomers. Currently, CLA available on the market today contains several different isomers and scientists are attempting to isolate the isomer responsible for the beneficial effects of CLA supplementation. In an investigation conducted by researchers at the University of Wisconsin-Madison, the trans-10, cis-12 isomer of CLA was found responsible for inducing body composition changes. Reduced body fat, enhanced body water, enhanced body protein, and enhanced body ash were associated with feeding the trans-10 cis-12 CLA isomer. In cell culture experiments, adipocytes had reduced lipoprotein lipase activity, intracellular triglyceride, and glycerol, and enhanced glycerol release into the medium as a result of the trans-10, cis-12 isomer. The cis-9, trans-11 and trans-9, trans-11 CLA isomers did not affect the biochemical markers that were tested. Thus, body composition changes are mediated by the trans-10, cis-12 CLA isomer-and it alone appears to be responsible for many of the biochemical effects of CLA.

Human Studies

Human data on CLA are at present limited. In one of the few trials available, Lowery et al. examined the effects of CLA in novice bodybuilders. Twenty-four men ingested 7.2 g/day of CLA or placebo (vegetable oil) while completing 6 weeks of bodybuilding exercise. After the trial was completed, gains in arm girth (corrected for skinfolds, body mass, and leg press strength were greater in the CLA-supplemented group than in the placebo group.

However, no differences were noted for subcutaneous fat (skinfolds), total body fat or body water distribution in either the intracellular or extracellular compartments. Further analysis of a subset of subjects revealed no difference in serum glucose, lipids, BUN, creatinine, LDH, SGOT, and SGPT enzymes.

In another trial, Kreider et al. further examined the effects of CLA supplementation and resistance-training on bone mineral content (BMC), bone mineral density (BMD), and markers of immune stress. In a double-blind and randomized trial, 23 experienced resistance-trained males were matched according to total body weight and training volume. Subjects were given supplements containing either 9 g/day of olive oil (placebo) or 6 g/day of CLA with 3.2 g/day of fatty acids for 28 days. Leukocytes from fasting whole blood were typed, and dual-energy x-ray absorptiometry (DEXA) determined whole body (excluding cranium) BMC and BMD on days a and 28 of supplementation. The results of this trial revealed a trend towards an increase in BMC in the CLA group. Some evidence suggested that CLA reduced the NeLy ratio suggesting less immune stress. The results provide some support to contentions that CLA supplementation may improve bone and immune status during resistance training in humans. However, additional research is necessary.

Safety and Toxicity

Long-term use of CLA in humans has not been evaluated; however, animal data collected from CLA studies and data on other essential fatty acids would indicate that supplementation is likely safe and may be beneficial to the overall health of athletes, especially in regard to disease prevention.

Studies of Conjugated Linoleic Acid (CLA)
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