Conjugated linoleic acid or CLA refers to a group of positional and geometric octadecadienoic acid isomers of linoleic acid. CLA is not a single substance. In contrast to linoleic acid, all the CLA isomers have conjugated bonds. In an unsaturated organic compound, two double bonds separated by a single bond are said to be conjugated. CLA is represented by the following structural formulas:
CLA is found naturally in animal tissues and food sources, including ruminant meats, poultry, eggs and dairy products, such as cheeses, milk and yogurt that have undergone heat processing treatments. Vegetable fats are generally poorer sources of CLA. However, CLA is produced from linoleic acid in safflower oil and sunflower oil by special treatment of these oils. CLA was originally found in milk fat where it exists in the form of phospholipids and triglycerides. Also, there is evidence that human milk contains CLA.
The principal dietary isomer of CLA is cis-9, trans-11 CLA, also known as rumenic acid and RA. This isomer is produced in the rumen of ruminant animals by microbial metabolism of linoleic and linolenic acids. Cis-9, trans-11 CLA may be absorbed directly or undergo further metabolism. Another CLA isomer, also found in ruminant tissue, is trans-10, cis-12 CLA. Most of the animal studies to date with CLA have used mixtures of CLA isomers that are mostly cis-9, trans-11 CLA and trans-10, cis-12 CLA in approximately equal amounts. Most commercial preparations of CLA contain cis-9, trans-11 CLA and trans-10, cis-12 CLA along with smaller amounts of other CLA isomers, including trans-9, cis-11 CLA, cis-10, cis-12 CLA, trans-9, trans-11 CLA, trans-10, trans-12 CLA and other isomers with conjugated double bonds at the 8, 10 and 11, 13 positions. The various isomers may produce different biologic effects.
Cis-9, trans-11 CLA is also known as c9, t11-octadecadienoic acid; trans-10, cis-12 CLA is also known as t10, c12-octadecadienoic acid. The term octadecadienoates is sometimes used synonymously with CLA.
Actions & Pharmacology
CLA may have anti-carcinogenic, anti-atherogenic, anti-diabetagenic and body composition-modifying activities in humans. These activities have been reported in experimental animals.
Mechanism of Action
The mechanism(s) of actions of CLA are not clearly understood. To reach a better understanding, it is necessary to determine the specific, possibly varying, effects of the different isomers. For example, the CLA-associated body composition changes observed in animals appear to be associated mainly with the trans-10, cis-12 CLA isomer. In mouse tissue culture, the trans-10, cis-12 CLA isomer was found to reduce lipoprotein lipase activity and concentrations of intracellular triglyceride. The trans-10, cis-12 isomer also decreased the expression of hepatic steroyl-CoA desaturase mRNA in one mouse study and the expression of stearoyl-CoA desaturase activity in mouse adipocytes in tissue culture in another study. Inhibition of stearoyl-CoA desaturase activity may depress fat synthesis.
Both cis-9, trans-11 and trans-10, cis-12 CLA isomers show anti-cancer activity. It is speculated that CLA may modulate eicosanoid activity as well as the activity of such cytokines as tumor necrosis factor-alpha. It is also speculated that activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) may play some role in the putative anti-diabetic activity of CLA. Activation of PPAR-gamma and/or PPAR-alpha may account, in part, for the anti-carcinogenic, lipid-lowering and anti-atherogenic effects of CLA reported in animal studies. The enzymes to produce the major isomers are being cloned in bacteria, and it is expected that with the availability of larger amounts of these materials, the effects and mechanisms of actions of these isomers, alone or in combination, will become clearer.
Little is currently known about the pharmacokinetics of CLA in humans. In experimental animals, the CLA isomers do get absorbed following digestion, but not much is known about CLA's metabolism subsequent to absorption. Some CLA appears to get incorporated into the phospholipids of cell membranes.
Indications & Usage
A hoped-for and early indicated CLA antiobesity effect is not supported by recent research. Similarly, inconsistent results make it impossible to conclude at present that CLA is an effective antiatherogenic agent. Some data suggest harmful effects from some CLA isomers. There is some evidence of anticancer activity and some suggestion of possible benefit in diabetes in a preliminary animal study. There is also, however, some equally preliminary evidence that CLA might be prodiabetic.
There are a few products with CLA available. The amounts of the two most studied isomers of CLA,cis-9, trans-11 and trans-10, cis-12 CLA, vary. Also, there are different amounts of other isomers of CLA in the various preparations. Typical doses are 1 to 2 grams daily. Some use doses up to 6 grams daily.
CLA is also being developed for use in functional foods.
LiteratureBanni S, Angioni E, Stefania M, et al. Conjugated linoleic acid and oxidative stress. J Am Oil Chem Soc. 1998;75:261-267.Belury MA. Conjugated linoleate: a polyunsaturated fatty acid with unique chemopreventive properties. Nutr Rev. 1995;53:83-89.Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and conjugated linoleic acid on human prostate cancer in SCID mice. Anticanc Res. 1998;18:833-838.de Deckere EA, van Amelsvoort JM, Mc Neill GP, Jones P. Effects of conjugated linoleic acid (CLA) isomers on lipid levels and peroxisome proliferation in the hamster. Br J Nutr. 1999;82:309-317.Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric mixture of conjugated linoleic acids but not pure cis-9, trans-11-octadecadienoic acid affects body weight gain and plasma lipids in hamsters. J Nutr. 2000;130:27-29.Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun. 1998;244:678-682.Kelley NS, Hubbard NE, Erickson KL. Conjugated linoleic acid isomers and cancer. J Nutr. 2007;137(12):2599-2607.Lee KN, Kritchevsky D, Pariza MW. Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclero. 1994;108:19-25.Lee KN, Pariza MW, Ntambi JM. Conjugated linoleic acid decreases hepatic stearoyl-CoA desaturase mRNA expression. Biochem Biophys Res Commun. 1998;248:817-821.McCarty MF. Downregulaton of macrophage activation by PPAR gamma suggests a role for conjugated linoleic acid in prevention of Alzheimer's disease. J Med Food. 1998;1:217-226.Mitchell PL, McLeod RS. Conjugated linoleic acid and atherosclerosis: studies in animal models. Biochem Cell Biol. 2008;86(4):293-301.Moya-Camarena SY, Belury MA. Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid. Nutr Rev. 1999;57:336-340.Ostrowski E, Muralitharan M, Cross RF. Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs. J Nutr. 1999;129:2037-2042.Pariza MW, Park Y, Cook ME. Conjugated linoleic acid and the control of cancer and obesity. Toxicol Sci. 1999;51(2 Suppl):107-110.Pariza MW, Park Y, Cook ME. Mechanisms of action of conjugated linoleic acid: evidence and speculation. Proc Soc Exp Biol Med. 2000;223:8-13.Pariza MW, Park Y, Kim S, et al. Mechanism of body fat reduction by conjugated linoleic acid. FASEB J. 1997;11:A139.Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body composition in mice. Lipids. 1997;32:853-858.Plourde M, Jew S, Cunnane SC, Jones PJ. Conjugated linoleic acids: why the discrepancy between animal and human studies? Nutr Rev. 2008;66(7):415-421.Silveira MB, Carraro R, Monereo S, et al. Conjugated linoleic acid (CLA) and obesity. Public Health Nutr. 2007;10(10A):1181-1186.van den Berg JJ, Cook NE, Tribble DL. Reinvestigation of the antioxidant properties of conjugated linoleic acid. Lipids. 1995;30:599-605.West DB, Delany JP, Camet PM, et al. Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse. Am J Physiol. 1998;275(3 Pt 2):R667-R672.Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW, Nelson GJ, eds. Advances in Conjugated Linoleic Acid Research. Volume 1. Champaign, IL:AOCS Press;1999.Further information:To keep track of CLA progress, an updated listing can be found on the Internet at http://www.wisc.edu/fri/clarefs.htm.
Research & Summary
Much of the early media ""buzz'' about CLA was related to claims that it could ""burn fat'' and fight obesity. In some early trials using animal obesity models, it was reported that CLA-enriched diets reduced body weight independent of food intake. Some CLA isomers were said to be more effective than others in fighting fat. Now, many years later, it appears that CLA does, in fact, reduce weight in some animal models but shows very little efficacy in humans. One recent review concluded: ""Experiments in humans have not been able to show a significant effect on body weight, body composition or weight regain related to either of the CLA isomers'' commonly promoted for this purpose. The trans-10, cis-12 and cis-9, trans-11 isomers have been combined in some weight-loss products. And, these reviewers cautioned, there is some data suggesting possible harm from the trans-10, cis-12 isomer in terms of negative effects on lipid profile, glucose metabolism and insulin sensitivity. Another recent review of CLA weight studies concluded that body weight loss is ""rarely observed'' with CLA supplementation in humans. These reviewers further make reference to ""the absence of confirmed or even plausible mechanisms'' by which CLA might promote weight loss in humans. They stated that CLA should not be recommended for this purpose.
CLA has shown some anticancer effects in a number of animal and in vitro studies. Proliferation of human malignant breast, colorectal, prostate, melanoma and lung cell lines has been inhibited by CLA. CLA has inhibited mammary tumorogenesis in a number of studies that demonstrate its efficacy in animal models independent of the amount and type of fat in the diet. In other experimental animal studies, it has significantly inhibited mouse forestomach neoplasia, epidermal tumors in mice and aberrant crypt foci in rat colon.
The mechanisms by which CLA exerts its anti-cancer effects are not yet understood, but it is evident that, in some cases, it appears to interact directly with carcinogens to reduce their potency and that, in other instances, it protects specific tissues through its interaction with those tissues, independent of the carcinogen. It appears to modulate carcinogenesis in all of its separate stages: initiation, promotion, progression.
At one time it was believed that CLA's anti-cancer and other therapeutic effects were largely due to an anti-oxidant property. More recent research demonstrated no significant CLA anti-oxidant effect. Instead, it is now believed by some that CLA exerts beneficial complex regulatory effects at the molecular level through its influence, among other things, on peroxisome proliferator-activated receptors (PPAR). The PPARs are nuclear receptors that modulate gene expression in response to fatty acids, some drugs and other substances. It is also believed to modulate eicosanoid and cytokine activity as well.
One group of researchers recently reported that high-CLA diets reduce the quantity of terminal end buds out of which mammary tumors develop. They further observe that CLA seems to inhibit cancer by selectively inhibiting rapidly dividing cells and by promoting programmed cell death or apoptosis.
More animal data have continued to accumulate, but, so far, meaningful clinical data related to a possible role of CLA in human cancers is lacking. Safety studies in human cancer conditions are needed before clinical trials can be launched. Some have expressed fear that some isomers or combination of CLA isomers might pose peril.
CLA's widely reported hypolipidemic effects (in animal studies) are also believed to be linked to the substance's influence on PPAR subtypes involved with lipid metabolizing enzymes and the modulation of plasma triglyceride clearance, among other things. Beneficial effects on lipids have been reported in rats, mice, rabbits, chickens, hamsters and in other animal models. Atheromatous lesions have regressed significantly in CLA-supplemented animals. And CLA has significantly reduced free fatty acids and triglycerides in Zucker diabetic fatty rats compared with fatty rats on control diets.
Despite some preliminary positive results, as discussed above, a recent review of the CLA atherosclerosis data concluded that after a decade of research no consensus has yet been reached on the potential for CLA to meaningfully modify atherosclerosis in animals, let alone in humans, where data is almost wholly lacking. There is no convincing evidence at this time, these reviewers concluded, that CLA reduces the incidence or severity of atherosclerotic lesions or that CLA can improve plasma lipid and lipoprotein levels. Moreover, as noted above, some researchers have observed that, in some circumstances, at least one CLA isomer exerted negative effects on lipid profile, glucose metabolism and insulin sensitivity.
In view of the latter, some preliminary indications that CLA might have benefit in a pre-diabetic animal model will need particularly careful follow-up.
Contraindications, Precautions & Adverse Reactions
CLA is contraindicated in those hypersensitive to any component of the preparation.
Because of lack of long-term safety data, CLA supplements should be avoided by children, pregnant women and nursing mothers.
At doses of up to 2 grams daily, occasional gastrointestinal complaints, such as nausea, have been noted.