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 9). 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 10). 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 11). The first studies to identify the antiadiposity characteristics of CLA were performed in laboratory mice 12). The t10,c12 isomer was found to be more effective as an antiadiposity agent, but this isomer caused a slight increase in insulin resistance 13), which generally was not observed when both the c9,t11 and t10,c12 isomers were given together 14).
Different CLA isomers are synthesized through a variety of mechanisms by bacteria and digesta present in the rumen 15). 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 16). 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 17). Many studies have shown unfavorable effects of CLA on lipoprotein levels, similar to that of other trans fatty acids 18), 19), whereas others have shown beneficial 20) or no effects 21). 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 22), but the results in humans are inconsistent 23), 24), 25), 26). 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 27), 28), as well as diabetic patients 29). In diabetic patients, CLA supplementation (3 g/d) showed negative effects on insulin and glucose metabolism and positive effects on serum HDL metabolism 30), triacylglycerol (TAG), and very low density lipoproteins (VLDL), but did not affect any other biochemical parameters 31). However, in another study it improved body composition, serum glucose, and insulin concentrations without having significant effects on lipid profile 32). In addition, CLA supplementation had no significant effects on lipid peroxidation and antioxidant metabolism among healthy volunteers 33), but had beneficial effects on oxidative stress among atherosclerotic patients 34).
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 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 35), insulin sensitivity in Zucker diabetic rat 36) and decreased atherosclerosis in hamsters 37). 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 38).
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 39). 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 40). Zucker diabetic fatty rats supplemented with 1.5% CLA also had significantly reduced body weight 41).
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. 42) 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 43), 44) found a significant reduction in body fat mass after 6 (−3.4%) 45) and 12 months (−8.7% CLA‐TG, −6.9% CLA‐FFA) 46) 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. 47) 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) 48).
Although it has been shown that CLA supplementation can lead to reductions in food intake 49), 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 50). CLA supplementation can increase energy expenditure 51) 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 52).
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 53). 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 54).
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 55). However, in healthy obese and non‐obese men and women, no change in body weight was observed 56). Furthermore, 3‐month daily ingestion of c9,t11 (3g/day) 57) and t10,c12 (3.4 g/day) 58) 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 59), increased HDL cholesterol and decreased the ratio of LDL : HDL cholesterol in type 2 diabetes 60), diminished incidence of atherosclerosis in sedentary young adults 61). Also c9,t11‐CLA supplementation lowered the risk of cardiovascular disease in men 62) 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 63). There was also a 35% reduction in the risk of colorectal cancer in women who consumed at least three servings of cheese/day 64). Noone et al. 65) 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 66). Very low density lipoprotein (VLDL) cholesterol concentrations were significantly reduced in the group receiving the 80 : 20 CLA blend 67). 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 68). 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 69). However, other studies have shown there to be no change in body composition 70) or immune function 71) 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.
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 72), 73). CLA has been shown to slightly increase biomarkers of inflammatory disease (usually within the published normal values), including C-reactive protein 74), white blood cell counts 75), and blood and urinary isoprostanes 76). Elevations of these biomarkers have been suggested to be indicators of inflammatory disease 77) but have also been shown to be antiinflammatory 78). 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 79). 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 80). This has been most notable in studies of short duration 81), those that used single isomers 82), 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 83). In a later study, the same enriched t10, c12 supplement was given for 18 weeks and did not result in insulin resistance 84). 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 85), and this may also be true compared with single isomer preparations. Further investigation into the safety of CLA is warranted.
References [ + ]
|1.||↵||Steinhart H, Rickert R, Winkler K. Identification and analysis of conjugated linoleic acid isomers (CLA). Eur J Med Res 2003; 8: 370–2. https://www.ncbi.nlm.nih.gov/pubmed/12915332|
|2.||↵||Wang Y, Jones PJ. Dietary conjugated linoleic acid and body composition. Am J Clin Nutr 2004; 79: 1153s–8s. https://www.ncbi.nlm.nih.gov/pubmed/15159250|
|3, 63, 64.||↵||Larsson SC, Bergkvist L, Wolk A. High‐fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography Cohort. Am J Clin Nutr 2005; 82: 894–900. https://www.ncbi.nlm.nih.gov/pubmed/16210722|
|4.||↵||Shokryzadan P, Rajion MA, Meng GY, Boo LJ, Ebrahimi M, Royan M, Sahebi M, Azizi P, Abiri R, Jahromi MF. Conjugated linoleic acid: a potent fatty acid linked to animal and human health. Crit Rev Food Sci Nutr. 2017;13:2737–2748. https://www.ncbi.nlm.nih.gov/pubmed/26252346|
|5.||↵||Fat burners: nutrition supplements that increase fat metabolism. Obesity reviews Volume 12, Issue 10, October 2011; Pages 841-851 https://onlinelibrary.wiley.com/doi/full/10.1111/j.1467-789X.2011.00908.x|
|6.||↵||Kepler CR, Hirons KP, McNeill JJ, Tove SB. Intermediates and products of the biohydrogenation of linoleic acid by Butyrinvibrio fibrisolvens. J Biol Chem 1966;241:1350–4 http://www.jbc.org/content/241/6/1350.long|
|7.||↵||Dhiman TR, Satter LD, Pariza MW, Galli MP, Albright K, Tolosa MX. Conjugated linoleic acid (CLA) content of milk from cows offered diets rich in linoleic and linolenic acid. J Dairy Sci 2000; 83: 1016–27. https://www.ncbi.nlm.nih.gov/pubmed/10821577|
|8, 9.||↵||Dhiman TR, Nam SH, Ure AL. Factors affecting conjugated linoleic acid content in milk and meat. Crit Rev Food Sci Nutr 2005;45:463–82 https://www.ncbi.nlm.nih.gov/pubmed/16183568|
|10.||↵||Christie WW, Dobson G, Adlof RO. A practical guide to the isolation, analysis and identification of conjugated linoleic acid. Lipids 2007;42:1073–84 https://www.ncbi.nlm.nih.gov/pubmed/17710464|
|11.||↵||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 https://www.ncbi.nlm.nih.gov/pubmed/10632956|
|12.||↵||Park Y, Albright KJ, Liu W. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997;32:853–8 https://www.ncbi.nlm.nih.gov/pubmed/9270977|
|13.||↵||Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care 2002;25:1516–21 https://www.ncbi.nlm.nih.gov/pubmed/12196420|
|14.||↵||Syvertsen C, Halse J, Hoivik HO, et al. The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese. Int J Obes (Lond) 2007;31:1148–54 https://www.ncbi.nlm.nih.gov/pubmed/17031391|
|15.||↵||Wallace RJ, McKain N, Shingfield KJ, Devillard E. Isomers of conjugated linoleic acids are synthesized via different mechanisms in ruminal digesta and bacteria. J Lipid Res 2007; 48: 2247–54. http://www.jlr.org/content/48/10/2247.long|
|16.||↵||Bruen R, Fitzsimons S, Belton O. Atheroprotective effects of conjugated linoleic acid. British Journal of Clinical Pharmacology. 2017;83(1):46-53. doi:10.1111/bcp.12948. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338159/|
|17.||↵||Wanders AJ, Brouwer IA, Siebelink E, Katan MB. Effect of a high intake of conjugated linoleic acid on lipoprotein levels in healthy human subjects. PLoS One. 2010;5:e9000. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815780/|
|18.||↵||Mensink RP. Metabolic and health effects of isomeric fatty acids. Curr Opin Lipidol. 2005;16:27–30. https://www.ncbi.nlm.nih.gov/pubmed/15650560|
|19.||↵||Wannamethee SG, Jefferis BJ, Lennon L, Papacosta O, Whincup PH, Hingorani AD. Serum Conjugated Linoleic Acid and Risk of Incident Heart Failure in Older Men: The British Regional Heart Study. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease. 2018;7(1):e006653. doi:10.1161/JAHA.117.006653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778956/|
|20.||↵||Wanders AJ, Brouwer IA, Siebelink E, Katan MB. Effect of a high intake of conjugated linoleic acid on lipoprotein levels in healthy human subjects. PLoS One. 2010;5:e9000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815780/|
|21.||↵||Tricon S, Yaqoob P. Conjugated linoleic acid and human health: a critical evaluation of the evidence. Curr Opin Clin Nutr Metab Care. 2006;9:105–110. https://www.ncbi.nlm.nih.gov/pubmed/16477173|
|22, 24.||↵||Xr Z, Ch S, Liu IR, Zhou D. Dietary conjugated linoleic acid increase PPAR gamma gene expression in adipose tissue of obese rat and improve insulin resistance. Growth Horm IGF Res. 2008;18:361–8. doi: 10.1016/j.ghir.2008.01.001 https://www.ncbi.nlm.nih.gov/pubmed/18304850|
|23, 29.||↵||Shadman Zh, Taleban F, Saadat N, Hedayat M. Effect of conjugated linoleic acid and vitamin E on glycemic control, body composition, and inflammatory markers in overweight type2 diabetics. J Diabetes Metab Disord. 2013;12:42. doi: 10.1186/2251-6581-12-42 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726499/|
|25.||↵||Venkatramanan S, Joseph SV, Chouinard PY, Jacques H, Farnworth ER, Jones PJ. Milk enriched with conjugated linoleic acid fails to alter blood lipids or body composition in moderately overweight, borderline hyperlipidemic individuals. J Am Coll Nutr. 2010;29:152–9. doi: 10.1080/07315724.2010.10719829 https://www.ncbi.nlm.nih.gov/pubmed/20679151|
|26.||↵||Smedman A, Vessby B. Conjugated linoleic acid supplementation in humans–metabolic effects. Lipids. 2001;36:773–81. doi: 10.1007/s11745-001-0784-7 https://www.ncbi.nlm.nih.gov/pubmed/11592727|
|27.||↵||Shama V, Jacques H, Me’lanie P, Patricia L, Roger S, Peter J. Conjugated linoleic acid supplementation for 8 weeks does not affect body composition, lipid profile, or safety biomarkers in overweight, hyperlipidemic men. J Nutr. 2011;141:1286–91. doi: 10.3945/jn.110.135087. https://www.ncbi.nlm.nih.gov/pubmed/21593349|
|28.||↵||Taylor JS, Williams SR, Rhys R, James P, Frenneaux MP. Conjugated linoleic acid impairs endothelial function. Arterioscler Thromb Vasc Biol. 2006;26:307–12. doi: 10.1161/01.ATV.0000199679.40501.ac. http://atvb.ahajournals.org/content/26/2/307.long|
|30.||↵||Moloney F, Yeow TP, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr. 2004;80:887–95 https://www.ncbi.nlm.nih.gov/pubmed/15447895|
|31.||↵||Noone EJ, Roche HM, Nugent AP, Gibney MJ. The effect of dietary supplementation using isomeric blends of conjugated linoleic acid on lipid metabolism in healthy human subjects. Br J Nutr. 2002;88:243–51. doi: 10.1079/BJN2002615 https://www.ncbi.nlm.nih.gov/pubmed/12207834|
|32.||↵||Colakoglu S, Colakoglu M, Taneli F, Cetinoz F, Turkmen M. Cumulative effects of conjugated linoleic acid and exercise on endurance development, body composition, serum leptin and insulin levels. J Sports Med Phys Fitness. 2006;46:570–7 https://www.ncbi.nlm.nih.gov/pubmed/17119522|
|33.||↵||Kim J, Park HD, Shin MJ, Park E. Eight weeks of conjugated linoleic acid supllementation has no effect on antioxidant status in healthy overweight/obese Korean individuals. Eur J Nutr. 2012;51:135–41. doi: 10.1007/s00394-011-0199-y. https://www.ncbi.nlm.nih.gov/pubmed/21541732|
|34.||↵||Eftekhari M, Aliasghari F, Babaei-Beigi M, Hasanzadeh J. Effect of conjugated linoleic acid and omega-3 fatty acid supplementation on inflammatory and oxidative stress markers in atherosclerotic patients. ARYA Atheroscler. 2013;9:311–8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933057/|
|35.||↵||Lee KN, Kritchevsky D, Pariza MW. Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclerosis 1994; 108: 19–25. https://www.ncbi.nlm.nih.gov/pubmed/7980704|
|36.||↵||Houseknecht KL, Vanden Heuvel JP, Moya‐Camarena SY, Portocarrero CP, Peck LW, Nickel KP, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun 1998; 244: 678–82. https://www.ncbi.nlm.nih.gov/pubmed/9535724|
|37.||↵||Nicolosi RJ, Rogers EJ, Kritchevsky D, Scimeca JA, Huth PJ. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters. Artery 1997; 22: 266–77. https://www.ncbi.nlm.nih.gov/pubmed/9209699|
|38.||↵||Gaullier JM, Berven G, Blankson H, Gudmundsen O. Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids 2002; 37: 1019–25. https://www.ncbi.nlm.nih.gov/pubmed/12558050|
|39, 50, 52.||↵||Park Y, Albright KJ, Liu W, Storkson JM, Cook ME, Pariza MW. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997; 32: 853–858.|
|40.||↵||Rahman SM, Wang Y, Yotsumoto H, Cha J, Han S, Inoue S et al. Effects of conjugated linoleic acid on serum leptin concentration, body‐fat accumulation, and beta‐oxidation of fatty acid in OLETF rats. Nutrition 2001; 17: 385–390.|
|41, 53.||↵||Houseknecht KL, Vanden Heuvel JP, Moya‐Camarena SY, Portocarrero CP, Peck LW, Nickel KP 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.|
|42.||↵||Malpuech‐Brugère C, Verboeket WP, Mensink RP, Arnal MA, Morio B, Brandolini M et al. Effects of two conjugated linoleic acid isomers on body fat mass in overweight humans. Obes Res 2004; 12: 591–598.|
|43, 45.||↵||Gaullier JM, Halse J, Hoivik HO, Hoye K, Syvertsen C, Nurminiemi M et al. Six months supplementation with conjugated linoleic acid induces regional‐specific fat mass decreases in overweight and obese. Br J Nutr 2007; 97: 550–560.|
|44, 46.||↵||Gaullier JM, Halse J, Hoye K, Kristiansen K, Fagertun H, Vik H et al. Conjugated linoleic acid supplementation for 1 year reduces body fat mass in healthy overweight humans. Am J Clin Nutr 2004; 79: 1118–1125.|
|47, 48.||↵||Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta‐analysis in humans. Am J Clin Nutr 2007; 85: 1203–1211.|
|49.||↵||Park Y, Albright KJ, Storkson JM, Liu W, Cook ME, Pariza MW. Changes in body composition in mice during feeding and withdrawal of conjugated linoleic acid. Lipids 1999; 34: 243–248.|
|51.||↵||West DB, Blohm FY, Truett AA, DeLany JP. Conjugated linoleic acid persistently increases total energy expenditure in AKR/J mice without increasing uncoupling protein gene expression. J Nutr 2000; 130: 2471–2477.|
|54.||↵||Ryder JW, Portocarrero CP, Song XM, Cui L, Yu M, Combatsiaris T et al. Isomer‐specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP‐2 gene expression. Diabetes 2001; 50: 1149–1157.|
|55.||↵||Belury MA, Mahon A, Banni S. The conjugated linoleic acid (CLA) isomer, t10c12‐CLA, is inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes mellitus. J Nutr 2003; 133: 257S–260S.|
|56.||↵||Smedman A, Vessby B. Conjugated linoleic acid supplementation in humans – metabolic effects. Lipids 2001; 36: 773–781|
|57.||↵||Riserus U, Vessby B, Arnlov J, Basu S. Effects of cis‐9,trans‐11 conjugated linoleic acid supplementation on insulin sensitivity, lipid peroxidation, and proinflammatory markers in obese men. Am J Clin Nutr 2004; 80: 279–283.|
|58.||↵||Riserus U, Vessby B, Arner P, Zethelius B. Supplementation with trans10cis12‐conjugated linoleic acid induces hyperproinsulinaemia in obese men: close association with impaired insulin sensitivity. Diabetologia 2004; 47: 1016–1019.|
|59.||↵||Racine NM, Watras AC, Carrel AL, Allen DB, McVean JJ, Clark RR, et al. Effect of conjugated linoleic acid on body fat accretion in overweight or obese children. Am J Clin Nutr 2010; 91: 1157–64. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854896/|
|60.||↵||Moloney F, Yeow TP, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr 2004; 80: 887–95 https://www.ncbi.nlm.nih.gov/pubmed/15447895|
|61.||↵||Eyjolfson V, Spriet LL, Dyck DJ. Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Med Sci Sports Exerc 2004; 36: 814–20. https://www.ncbi.nlm.nih.gov/pubmed/15126715|
|62.||↵||Riserus U, Vessby B, Arnlov J, Basu S. Effects of cis‐9,trans‐11 conjugated linoleic acid supplementation on insulin sensitivity, lipid peroxidation, and proinflammatory markers in obese men. Am J Clin Nutr 2004; 80: 279–83. https://www.ncbi.nlm.nih.gov/pubmed/15277146|
|65, 67.||↵||Noone EJ, Roche HM, Nugent AP, Gibney MJ. The effect of dietary supplementation using isomeric blends of conjugated linoleic acid on lipid metabolism in healthy human subjects. Br J Nutr 2002; 88: 243–51. https://www.ncbi.nlm.nih.gov/pubmed/12207834|
|66.||↵||Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglyceride concentration and ischemic heart disease: an eight‐year follow‐up in the Copenhagen Male study. Circulation 1998; 97: 1029–36 http://circ.ahajournals.org/content/97/11/1029.long|
|68.||↵||Song HJ, Grant I, Rotondo D, Mohede I, Sattar N, Heys SD, et al. Effect of CLA supplementation on immune function in young healthy volunteers. Eur J Clin Nutr 2005; 59: 508–17. https://www.ncbi.nlm.nih.gov/pubmed/15674307|
|69.||↵||Turpeinen AM, Ylonen N, von Willebrand E, Basu S, Aro A. Immunological and metabolic effects of cis‐9, trans‐11‐conjugated linoleic acid in subjects with birch pollen allergy. Br J Nutr 2008; 100: 112–9. https://www.ncbi.nlm.nih.gov/pubmed/18167173|
|70.||↵||Malpuech‐Brugere C, Verboeket‐van de Venne WP, Mensink RP, Arnal MA, Morio B, Brandolini M, et al. Effects of two conjugated linoleic Acid isomers on body fat mass in overweight humans. Obes Res 2004; 12: 591–8 https://www.ncbi.nlm.nih.gov/pubmed/15090626|
|71.||↵||Nugent AP, Roche HM, Noone EJ, Long A, Kelleher DK, Gibney MJ. The effects of conjugated linoleic acid supplementation on immune function in healthy volunteers. Eur J Clin Nutr 2005; 59: 742–50. https://www.ncbi.nlm.nih.gov/pubmed/15827560|
|72.||↵||Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids. 2002 Nov;37(11):1019-25. https://www.ncbi.nlm.nih.gov/pubmed/12558050|
|73.||↵||Conjugated linoleic acid and obesity control: efficacy and mechanisms. Int J Obes Relat Metab Disord. 2004 Aug;28(8):941-55. https://www.ncbi.nlm.nih.gov/pubmed/15254484|
|74.||↵||Riserus U, Basu S, Jovinge S, Fredrikson GN, Arnlov J, Vessby B. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance. Circulation 2002;106:1925–9.|
|75.||↵||Gaullier JM, Halse J, Høye K, et al. .Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005;135:778–84.|
|76, 83.||↵||Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care 2002;25:1516–21.|
|77.||↵||Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–12|
|78.||↵||Musiek ES, Gao L, Milne GL, et al. .Cyclopentenone isoprostanes inhibit the inflammatory response in macrophages. J Biol Chem 2005;280:35562–70|
|79, 81.||↵||Moloney F, Yeow TP, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr 2004;80:887–95.|
|80.||↵||Treatment With Dietary trans10cis12 Conjugated Linoleic Acid Causes Isomer-Specific Insulin Resistance in Obese Men With the Metabolic Syndrome. Diabetes Care 2002 Sep; 25(9): 1516-1521. https://doi.org/10.2337/diacare.25.9.1516|
|82.||↵||Riserus U, Vessby B, Arnlov J, Basu S. Effects of cis-9,trans-11 conjugated linoleic acid supplementation on insulin sensitivity, lipid peroxidation, and proinflammatory markers in obese men. Am J Clin Nutr 2004;80:279–83.|
|84.||↵||Malpuech-Brugere C, Verboeket-van de Venne WP, Mensink RP, et al. .Effects of two conjugated linoleic acid isomers on body fat mass in overweight humans. Obes Res 2004;12:591–8.|
|85.||↵||Gaullier JM, Berven G, Blankson H, Gudmundsen O. Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids 2002;37:1019–25|