Conjugated linoleic acid (CLA) is a collective term used to describe a set of 28 distinct positional and geometric isomers of linoleic acid (18:2) [1-3]. CLA is formed when reactions shift one or both of the double bonds of linoleic acid so that the two double bonds are no longer separated by two single bonds [4]. Each double bond can be in either cis or trans configuration and in any position on the carbon chain, although they are most commonly found in positions 8 and 10, 9 and 11, 10 and 12, or 11 and 13. Synthesized CLA usually contains predominantly the cis-9, trans-11 (c9,t11, also known as rumenic acid) and trans-10, cis-12 (t10,c12) isomers [1].
CLA is a common dietary component, with the main sources being beef, lamb, and dairy products [1-2]. The amount of CLA varies depending on animal breed, product processing, and animal feeding conditions, and the amount in dairy products, for example, typically falls in the range of 2.9 to 8.92 mg per gram of fat [1, 4]. In contrast to synthetic CLA, naturally occuring CLA usually consists of over 90% of the c9,t11 isomer, followed by the t7,c9; c11,t13; c8,t10; and t10,c12 isomers [2]. Estimated average intake of CLA in the US is 150 mg/day for women and 200 mg/day for men, although this amount can vary considerably within the range of 15-650 mg per day [1-2].
When extra CLA is provided in the diet, it accumulates in tissues of animals and humans. This effect is tissue dependent, with the highest accumulation in adipose and lung tissue [2, 4]. A multitude of physiological effects have been identified, including effects on body composition, serum glucose and insulin, carcinogenesis, cardiovascular variables, bone formation, and immune function [2]. Additionally, CLA isomers can be elongated and desaturated within the body, and these metabolites may have even further effects which are not yet well identified or understood, although they may play an important role in the effects CLA has on carcinogenesis [2, 5].
CLA and body composition
CLA has quite pronounced effects on fat loss. This effect has been seen in mice, hamsters, rats, chickens, dogs, and pigs [1-2], and in several of these models body fat loss is seen regardless of the type or quantity of dietary fat [4]. However, the degree varies depending on species, strain, age, gender, dosage, duration, and most importantly CLA isomer composition. In a study in mice, 1.5 g/kg resulted in 10% body weight reduction and 70% body fat reduction relative to placebo [1]. Additionally, in mice, it was found that the fat reduction occurs regardless of food intake or fat level, indicating that CLA may be effective even in lean individuals or those in a hypercaloric state [2].
There have also been 19 randomized, double-blind, placebo-controlled studies in humans (12 of which were published in peer reviewed journals) that have yielded varying results. A recent review of 13 of these studies found that there was no effect on body weight in any of them, but three found decreased fat mass and one found increased fat-free mass [1]. These differential results may be due to age and sex specific effects [2], as well as differences in dosage, isomers used, and study design (the optimal dosage will be discussed in the last section). Many of these studies used a small sample population, in which it is more difficult to achieve statistically significant results.
Many mechanisms of action have been identified. Fat loss is attributed to the t10,c12 isomer [1-2, 4]. Although CLA does not acutely increase energy expenditure, it does so when administered chronically, and is associated with higher levels of norepinephrine [1-2]. Three relatively consistent effects of CLA supplementation associated with fat loss are decreased triglyceride in****oration in adipocytes, modulation of differentiation of adipocytes (possibly via decrease in expression of PPAR gamma), and induction of apoptosis in both brown and white adipose tissue [1-2, 6]. All of these effects have been noted both in vitro and in vivo, and the latter effect is associated with induction of TNF-alpha and UCP-2 [2]. Other effects noted have been inhibition of LPL and fatty acid synthetase, in vivo and in vitro respectively [2, 7]. Finally, the t10,c12 isomer inhibits stearoyl-CoA desaturase 1 and thus results in a higher ratio of monounsaturated fats to saturated fats, which may inhibit adipogenesis [1]. Despite all of these effects, results are often inconsistent between species and strains, and it has been postulated that a consistent mechanism of action may not even exist [4].
Other properties of CLA
Inhibition of carcinogenesis - Even more established than the influence CLA has on body composition is the effect it has on carcinogenesis. In vivo inhibition of skin cancer, forestomach neoplasia, and prostate, colon, pancreatic, and mammary cancers have all been established in various animal models [2, 4, 8]. In vitro, CLA also inhibits the development of human liver, lung, and gastric cancers [3, 9].
The mechanisms of action are not well established and may be differential. In contrast to the effect on body fat, the c9,t11 and t10,c12 isomers may both be involved in different ways. During initiation, CLA may regulate free radical-induced oxidation, carcinogen metabolism, and/or carcinogen-DNA adduct formation. CLA also inhibits cancer proliferation, but the mechanism of action is even less understood. It is known to promote apoptosis in cancer cells, and the effect may also be due to modulation of cell differentiation [2]. Regulation of phospholipid metabolism and gene expression may also play roles [4, 10]. Also, in addition to the direct impact on carcinogenesis, CLA may facilitate cancer prevention in more indirect ways – body fat accumulation increases cancer risk, as does cachexia, and inhibition of these processes by CLA may play a role [5].
Cardiovascular effects - The effects CLA has on cardiovascular variables are inconsistent, especially in humans. It is noteworthy that CLA is technically a trans fat, and therefore may have some of the same consequences as other trans fats [1]. In both rabbits and hamsters fed hypercholesterolemic diets, CLA inhibits atherosclerotic plaque formation and reduces both total and LDL cholesterol levels [1-2]. CLA also suppresses hypertension in rats [11]. In contrast, CLA increases the formation of arterial fatty streak formation in mice [1-2]. In studies on fat loss in humans in which cholesterol levels were monitered, there is either no effect or a minor effect and the results are inconsistent [1], but one study on lipid metabolism in humans indicated that different isomeric blends of CLA improved triacylglycerol and VLDL metabolism [12].
Insulin resistance - Proponents of CLA often quote studies in which it improves insulin sensitivity in rat models of diabetes [1-2, 4]. Additionally, CLA favorably alters metabolic parameters in humans with type II diabetes [2]. Unfortunately the opposite effect is seen in nondiabetic individuals. Induction of insulin resistance, or markers thereof, has been noted in pigs, mice, hamsters, and rats fed CLA despite fat loss [1-2, 4]. Even in a study in pigs in which there were no changes in body composition, fasting insulin rose by 37% [4]. Additionally, 3.4 g daily of t10,c12 CLA for 12 weeks increased insulin resistance (by 19%) and C-reactive protein (a marker of inflammation and predictor of cardiovascular risk) in obese men [1, 13]. This effect may be related with increased levels of TNF-alpha [4]. It can be concluded that although CLA is beneficial to those with diabetes, it may increase insulin resistance in normoglycemic individuals.
Other effects - There are a variety of other effects of CLA. On the positive side, CLA reduces bone inflammation [14] and has a positive role in bone formation in rats [2]. CLA also appears to improve immune response in healthy men [15] and protects against end-stage symptoms of lupus erythematosis, although it accelerates the onset of this condition [2]. Multiple studies have found CLA to increase markers of lipid peroxidation and oxidative stress in both healthy and obese humans, an effect which is not reduced by vitamin E [1-2, 16-17]. Additionally, CLA causes liver steatosis (fat accumulation) in mice and chicken and liver and kidney enlargement in hamsters despite a decrease in body weight, and this effect has been attributed to the t10,c12 isomer [1-2, 18].
Dosage and administration
For fat loss, the t10,c12 isomer is the important one, and the amount of this isomer present in studies in which significant fat loss was seen ranges from .5-2.5 g for 4-12 weeks (note that this is equivalent to about 2.5-12.5 g of CLA powder or 1.5-7.5 g of 30% t10,c12 CLA oil). More significant fat loss would be seen if the dosage was closer to that used in animal studies (which would be equivalent to upwards of 25 g of CLA oil daily [1]), but the risk of liver enlargement and insulin resistance will be proportionally increased, so this quantity is not recommended (nor is it economically feasible for most). It would be wiser to use a lower dose of CLA in conjunction with other fat loss agents, and monitor glucose and insulin levels and liver parameters if possible. Side effects reported in clinical trials include gastrointestinal discomfort and fatigue [4].
