CLA

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cla

What is CLA

CLA (conjugated linoleic acid) is a naturally occurring trans fatty acids with 18-carbon that has reported to promote weight loss by unknown mechanisms. Conjugated linoleic acid (CLA) is a mixture of the Omega-6 essential fatty acid isomers of linoleic acid (C18:2 n-6). Cis-9,trans-11 (c9,t11) is the major isomer which is mostly found in the ruminant meats (beef and lamb) and dairy products (milk and cheese) 1. The major source of CLA in the human diet is through the consumption of ruminant meats such as beef and lamb 2 and from high fat dairy products such as whole milk (3% fat), full fat cultured milk, mainly sour milk (3% fat), cheese, mainly hard cheese (28% fat), cream (40% fat), full fat sour cream (34% fat), reduced fat sour cream (17% fat) and butter (80% fat) 3. Dairy products are a primary source of cis‐9, trans‐11‐CLA (c9,t11‐CLA), the most prevalent CLA isomer, in the diet of humans 4. It has been suggested that CLA can act as an anti-obesity agent through its ability to decrease energy and food intake, decrease lipogenesis and increase energy expenditure, lipolysis and fat oxidation 5.

CLA is naturally synthesized from linoleic acid by ruminant animals 6. Grass fed cattle produce the highest levels of CLA. Cattle fed a diet rich in polyunsaturated fatty acids have increased concentrations of CLA in their milk 7; however, human dietary intake from these sources is estimated at 0.1–1.1% of ruminant animal fat leading to possible total intakes of 15–440 mg of CLA/day 8. For larger doses, CLA supplements can be commercially prepared from plant oils containing high amounts of linoleic acid.

There are many CLA isomers. The most common naturally occurring in dairy fat and meat from ruminant animals is the cis-9, trans-11(c9,t11) isomer 8. The cis-9, trans-11 and trans-10, cis-12 (t10,c12)-CLA can also be commercially synthesized from linoleic acid–rich oils such as sunflower and safflower oil 9. These are considered the most physiologically active isomers, and the 50:50 mixture has been shown to be the most effective for weight management or body fat reduction 10. The first studies to identify the antiadiposity characteristics of CLA were performed in laboratory mice 11. The t10,c12 isomer was found to be more effective as an antiadiposity agent, but this isomer caused a slight increase in insulin resistance 12, which generally was not observed when both the c9,t11 and t10,c12 isomers were given together 13.

Different CLA isomers are synthesized through a variety of mechanisms by bacteria and digesta present in the rumen 14. There are 28 known CLA isomers with trans-11, cis- (t11,c9)‐CLA, which accounts for 80% of CLA intake in the diet and trans-10, cis-12 (t10,c12)‐CLA being the two most abundant 15. The biological activities of CLA have received considerable attention over the past number of years due to their documented anti‐cancer, anti‐inflammatory, anti‐atherogenic and anti‐diabetic effects in animal studies. However, in human studies, evidence on the antiatherosclerotic effects of CLA remains contradictory 16. Many studies have shown unfavorable effects of CLA on lipoprotein levels, similar to that of other trans fatty acids 17, 18, whereas others have shown beneficial 19 or no effects 20. Some researchers postulated that it is possible that the 2 isomers – c9,t11‐CLA isomer principal dietary form of CLA, accounting for as much as 85% to 90% of total CLA in dairy products and the trans‐10, cis‐12‐CLA isomer not produced in detectable amounts naturally but is found in larger amounts as a product of commercial CLA synthesis, may have differing effects on cardiovascular risk. Many of the studies on the effects of CLA on cardiovascular risk factors have focused on supplementary CLA, which commonly consists of roughly 50:50 portions of c9,t11‐CLA and trans‐10, cis‐12‐CLA. This may account for the inconsistencies seen between studies on the effects of CLA on cardiovascular risk factors.

It has also been claimed but yet to be proven in clinical studies that eating CLA could reduce your body fat and thus make you lose weight. Animal studies have shown that CLA supplementation reduces body weight and body fat mass and improves glycemic status and lipid profiles 21, but the results in humans are inconsistent 22, 21, 23, 24. CLA has shown no significant effects on lipid profile, fasting blood glucose, insulin resistance, body composition, and body mass index (BMI) among healthy and hyperlipidemic overweight and obese participants 25, 26, as well as diabetic patients 22. In diabetic patients, CLA supplementation (3 g/d) showed negative effects on insulin and glucose metabolism and positive effects on serum HDL metabolism 27, triacylglycerol (TAG), and very low density lipoproteins (VLDL), but did not affect any other biochemical parameters 28. However, in another study it improved body composition, serum glucose, and insulin concentrations without having significant effects on lipid profile 29. In addition, CLA supplementation had no significant effects on lipid peroxidation and antioxidant metabolism among healthy volunteers 30, but had beneficial effects on oxidative stress among atherosclerotic patients 31.

One specific isoform of CLA, trans-10, cis-12 (t10,c12) CLA, is associated with reduced adiposity, which is beneficial, while simultaneously promoting systemic inflammation, insulin resistance, and dyslipidemia, all of which could be detrimental. These seemingly opposing effects of t10,c12-CLA have not yet been examined in the context of the metabolic syndrome, a common condition in which visceral obesity is associated with adipose tissue inflammation, dyslipidemia, and insulin resistance. Commercially available CLA supplements containing trans-10, cis-12-CLA are widely used to facilitate weight loss, so the opposing effects on body weight and inflammation could put consumers at risk of the potential for long-term adverse health effects. It is therefore important to better understand mechanisms by which t10,c12-CLA affects adipose tissue metabolism. Preliminary studies have begun to investigate mechanisms by which trans-10, cis-12-CLA reduces adiposity. Scientists have determined that mitochondrial metabolism is substantially increased in cultured adipocytes, with concomitant increases in inflammatory and monocyte chemotactic factor gene expression. Specifically, mitochondrial fatty acid oxidation is enhanced by trans-10, cis-12 (t10,c12) CLA in white adipocytes, a process normally reserved for brown adipocytes, skeletal muscle, cardiac muscle, and hepatocytes. Current hypothesis is that trans-10, cis-12 (t10,c12) CLA contributes to impaired lipid storage in adipose tissue by altering the lipid metabolism of white adipocytes towards a unique brown adipocyte-like phenotype at the expense of causing inflammatory changes in adipose tissue. Scientists are currently examining the effects of t10,c12-CLA on adipocyte lipid metabolism and inflammation as it relates to the metabolic state frequently associated with obesity.

CLA benefits

CLA isomers have been found to have both synergistic and antagonistic effects on cellular functions resulting in alterations in function and metabolism. The effect of the isomers has been notably different between strains of animals and species, where CLA is primarily associated with advantages to health showing reduced adiposity, improved metabolism of plasma lipoprotein in rabbits 32, insulin sensitivity in Zucker diabetic rat 33 and decreased atherosclerosis in hamsters 34. Unfortunately, not all of these health benefits in animal models have translated well into clinical studies investigating the effects of CLA on human health. However, CLA blends enriched in c9,t11 and t10,c12 isomers have been identified as safe and effective in humans 35.

Alterations in body mass, composition and fat oxidation

Rodent studies have observed alterations in body weight and composition when the ad libitum diet is supplemented with CLA. Mice supplemented with 0.5% CLA exhibited 60% reductions in body fat and 14% increases in lean body mass compared to controls 36. Similarly, when young rats were supplemented with 1% CLA for 4 weeks, body weight gain was significantly reduced with reductions of 44% in fat pad size 37. Zucker diabetic fatty rats supplemented with 1.5% CLA also had significantly reduced body weight 38.

On the basis of the results from animal studies, there is potential for CLA to have weight loss effects in humans. Malpuech‐Brugère et al. 39 conducted a study investigating the effects of two CLA isomers (c9,t11 and t10,c12) on body fat mass. After a 6‐week run‐in period, consuming high oleic sunflower oil (3 g) daily, overweight healthy men were allocated into one of five groups. These five groups included daily consumption of high (3 g) and low (1.5 g) doses of CLA isomers c9,t11 and t10,c12 daily for 18 weeks, plus a placebo control group. Following the intervention period there were no significant changes, among all five of the treatments groups, in body fat mass and other body composition parameters (body mass index, weight, per cent body fat). More recent studies where chronic CLA supplementation has been administered, as a mixture containing both CLA isomers c9,t11 and t10,c12, have found favourable effects on body composition. Gaullier and colleagues 40, 41 found a significant reduction in body fat mass after 6 (−3.4%) 40 and 12 months (−8.7% CLA‐TG, −6.9% CLA‐FFA) 41 of CLA supplementation compared to placebo. The interest in CLA, as a body fat regulator, has resulted in many studies differing in CLA isomers, dose and study duration. Whigham et al. 42 performed a meta‐analysis of 18 studies which had all investigated the influence of CLA on improving body composition. Based on three studies, a conclusion cannot be made on supplementation of single CLA isomers (c9,t11 and t10,c12) and their potential to reduce body fat. However, this meta‐analysis concluded that 3.2 g CLA per day is effective in producing modest fat loss (0.05±0.05 kg per week) 42.

Although it has been shown that CLA supplementation can lead to reductions in food intake 43, this is usually not sufficient to account for the changes in body mass and even without reductions in food intake, reductions in body fat mass are apparent 36. CLA supplementation can increase energy expenditure 44 to a level sufficient to induce body fat loss and although it has been observed that CLA supplementation can increase UCP2 expression, this is not thought to be a valid mechanism. Rodent studies have provided evidence that the alterations in body composition and fat oxidation were associated with increases in CPT activity in brown adipose tissue, skeletal muscle and liver by up to 2.5 times that of the control, with increased rates of lipolysis being evident 36.

In addition to the actions of CLA on fat oxidation and weight loss, there are claims that CLA can benefit those with impaired glucose tolerance. Initial studies using Zucker diabetic fatty rats with a feeding schedule of 1.5% CLA for 14 days have shown normalized glucose tolerance and attenuated fasting hyperinsulinemia and plasma fatty acid concentrations 38. This effect appears to occur at the level of the adipocyte via the activation of PPAR‐γ. The observed response is also isomer‐specific with the t10,c12 isomer being more effective than the c9,t11 isomer 45.

While the effects of CLA supplementation in rodents appear positive, the effects in humans are inconsistent. In patients with non‐insulin‐dependent diabetes mellitus, 6g/day of CLA for 2 weeks was associated with a correlation between body weight and plasma concentrations of the isomer t10,c12 46. However, in healthy obese and non‐obese men and women, no change in body weight was observed 47. Furthermore, 3‐month daily ingestion of c9,t11 (3g/day) 48 and t10,c12 (3.4 g/day) 49 has been found to significantly lower insulin sensitivity (−15% in both treatment groups) in overweight Caucasian men. As insulin resistance and obesity are associated with the metabolic syndrome, increasing the risk of life‐threatening diseases, CLA may not be suitable as a weight‐regulating supplement. The biological effects of CLA are isomer‐dependent and cis‐9,trans‐11 and trans‐10,cis‐12 may have distinctly different effects. It is also likely that some effects are induced and/or enhanced by these isomers acting synergistically. It has been suggested that the trans‐10,cis‐12 isomer is responsible for reduction in body fat and is also referred to as the most effective isomer affecting blood lipids.

CLA dietary supplementation, using a 50 : 50 blend of c9,t11 : t10 , c12‐CLA, has shown reductions in fat mass in both overweight and obese adults and children 50, increased HDL cholesterol and decreased the ratio of LDL : HDL cholesterol in type 2 diabetes 51, diminished incidence of atherosclerosis in sedentary young adults 52. Also c9,t11‐CLA supplementation lowered the risk of cardiovascular disease in men 53 and it was found that women who consumed four or more servings of high fat dairy foods rich in CLA reduced their risk of developing distal colon cancer by 34%, when compared with women who consumed less than one serving per day 3. There was also a 35% reduction in the risk of colorectal cancer in women who consumed at least three servings of cheese/day 3. Noone et al. 54 investigated the effects of CLA on cardiovascular disease risk factors in 51 healthy human subjects. In this 8 week, randomized, double‐blind placebo study, c9,t11‐CLA and t10,c12‐CLA isomers were investigated using linoleic acid as the control. The group receiving the 50 : 50 CLA blend showed significantly decreased fasting plasma triacylglycerol concentrations. Elevated plasma triacylglycerol concentrations are a risk factor of ischaemic heart disease 55. Very low density lipoprotein (VLDL) cholesterol concentrations were significantly reduced in the group receiving the 80 : 20 CLA blend 54. The effects of CLA supplementation on the immune system were investigated in 28 young healthy volunteers. In this 12 week study, volunteers received a dietary supplement of 3 g/day of c9,t11 : t10,c11‐CLA blend (50 : 50). In CLA supplemented volunteers there was a significant increase in the anti‐inflammatory cytokine IL‐10, a decrease in pro‐inflammatory cytokines TNF‐α and IL‐1β and a decrease in delayed‐type hypersensitivity response 56. Interestingly in a separate study in humans with birch pollen allergy, c9,t11‐CLA supplementation (2 g/day, 12 weeks) significantly reduced granulocyte M‐CSF (GM‐CSF), a known driver of the pro‐inflammatory MΦ1 phenotype 57. However, other studies have shown there to be no change in body composition 58 or immune function 59 following CLA supplementation. There is a need for further rigorous clinical investigation into the benefits of CLA supplementation and for characterization of the optimum blend of CLA to use in humans.

Summary

In summary, it would appear that the majority of information with regards to the effects of CLA on altering body weight and composition has been gained from experiments on animals. In human studies, modest fat loss may be achieved through long‐term supplementation of ∼3 g/day CLA. Future studies should also address the safety issues.

CLA side effects

Although no severe adverse events have been related to the use of CLA, there are reports of effects of CLA on several risk factors for chronic disease 60, 61. CLA has been shown to slightly increase biomarkers of inflammatory disease (usually within the published normal values), including C-reactive protein 62, white blood cell counts 63, and blood and urinary isoprostanes 64. Elevations of these biomarkers have been suggested to be indicators of inflammatory disease 65 but have also been shown to be antiinflammatory 66. Thus, although CLA has been shown to cause a modest increase in inflammatory markers, it has also been shown to decrease inflammatory disease in several animal models. The relevance of these elevated biomarkers of inflammation taking into account the decrease in inflammatory disease remains to be determined.

CLA has also been reported to increase insulin resistance 67. The trans‐10, cis‐12‐CLA isomer but not a CLA mixture, significantly increased insulin resistance, fasting glucose, and dyslipdemia in abdominally obese men. Such men are prone to develop type 2 diabetes and trans‐10, cis‐12‐CLA might be diabetogenic in the metabolic syndrome 68. This has been most notable in studies of short duration 67, those that used single isomers 69, or both. For example, in one study, insulin resistance was reported in individuals supplemented with only the t10, c12 isomer for 12 weeks, but not with a mixed preparation of predominantly the c9, t11 and t10, c12 isomers 64. In a later study, the same enriched t10, c12 supplement was given for 18 weeks and did not result in insulin resistance 70. With regard to both safety and efficacy, it has been suggested that CLA preparations enriched in c9, t11 and t10, c12 isomers are preferable to preparations containing 4 isomers 71, and this may also be true compared with single isomer preparations. Further investigation into the safety of CLA is warranted.

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