Obesity and its related health problems, like type 2 diabetes and cardiovascular disease, are putting a huge strain on healthcare systems. This has led to a search for new and effective ways to lose weight. While lifestyle changes such as exercise and cutting calories can work in the short term, many people struggle to keep the weight off long term. This is why there's an urgent need for alternative methods that can help people achieve lasting weight loss.
Conjugated linoleic acid (CLA) is a fatty acid that occurs naturally in food products from ruminant animals. It has been identified as a possible agent against obesity, showing significant effectiveness in mice and some effectiveness in humans with obesity. Originally recognized for its potential to fight cancer, CLA has also been found to have properties that combat hardening of the arteries. This article will examine both pre-clinical and human studies on CLA, suggesting its potential benefits against cancer, obesity, and atherosclerosis.
What is CLA?
Conjugated linoleic acids (CLAs) are polyunsaturated fatty acids that are naturally present in food products from ruminant animals. There are at least 28 known isomers of CLA, distinguished by two conjugated double bonds in different geometric (cis or trans) and positional locations. The most common of these are 18:2cis-9, trans-11 (9,11 CLA, or rumenic acid), making up about 85%, and 18:2trans-10, cis-12 (10,12 CLA), representing around 10% of all naturally occurring CLA isomers.
CLAs come from the biohydrogenation of linoleic acid (18:2cis-9, cis-12) by bacteria that produce linoleic acid isomerase, which are abundant in ruminant bacteria. Therefore, foods from ruminant sources, such as beef, lamb, butter, and dairy products, are natural sources of CLA. CLA can also be produced synthetically from oils rich in linoleic acid, such as safflower, sunflower, corn, and soybean oils, using an alkaline-catalyzed reaction to convert linoleic acid into CLA. This synthetic preparation results in a different proportion of the most common CLA isomers, yielding approximately 40%-45% 9,11 CLA and 40%-45% 10,12 CLA, with the remainder consisting of small amounts of other CLA isomers.
Because CLAs have one double bond in the trans configuration, they are technically considered trans fatty acids. However, the United States Food and Drug Administration (FDA) does not classify CLA as a trans-fat. In 2008, CLA was given a “Generally Regarded as Safe (GRAS)” designation by the FDA, exempting it from being classified as a trans-fat on nutrition labels. Studies in humans suggest that while the consumption of industrially produced trans fats may be positively correlated with coronary heart disease risk factors, the consumption of ruminant-derived trans fats, such as CLA, does not, and may even be negatively associated with cardiovascular disease.
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CLA Production in Ruminants
Polyunsaturated fatty acids (PUFAs) like linoleic acid (C18:2), which are abundant in typical livestock feed, grass, and hay, can be toxic to many rumen bacteria. As a result, most dietary PUFAs undergo biohydrogenation in the rumen through a series of fatty acid intermediates, ultimately producing less toxic saturated fat (in this case, stearic acid, C18:0). During this biohydrogenation process of PUFAs, intermediate by-products such as 9,11 and 10,12 CLA are generated.
The CLA content of ruminant food products depends on factors like the type of feed, age and breed of the animal, environmental season, and rumen pH. Feed such as grass or corn contains higher levels of PUFA, resulting in a higher CLA content in the animal. The spring and summer months usually yield the highest CLA levels, reportedly nearly double the levels achieved during the winter. Grain consumption decreases the rumen pH, reducing the abundance of the key rumen bacteria linoleic acid isomerase activity; conversely, grass feeding promotes a more favorable rumen environment for CLA-producing bacteria.
CLA consumption has many purported health benefits, including anti-carcinogenicity, anti-obesogenicity, and anti-atherogenicity. Efforts have been made to increase the CLA content of ruminant food products for some time. However, it was quickly observed that cows fed diets designed to increase their endogenous CLA content had a depressed milk fat production. A study in which Holstein cows were fed diets supplemented with partially hydrogenated soybean oil, resulting in a high intake of CLA, showed a significant correlation between the depression of milk fat and the ruminal content of trans10-18:1, a fatty acid metabolite of which 10,12 CLA is a direct precursor. Subsequent studies concluded that the increased ruminant CLA production led to decreased de novo fatty acid synthesis in the mammary tissue of cows, the first indication that CLA inhibits lipogenesis, an effect now attributed to the 10,12 CLA isomer specifically.
The fortification of dairy products, such as yogurt, milk, and cheese, with CLA (usually mixed CLA) is another method by which humans can increase their CLA consumption; however, few studies have examined the impact of such CLA-fortified foods on human health. Fueled by the purported health benefits imparted by CLA as well as the booming nutraceutical industry, CLA has now been widely marketed as a nutritional supplement.
Potential Health Benefits of CLA
Anti-Carcinogenic Effects
One of the first beneficial effects attributed to CLA was its anti-carcinogenicity, discovered by Michael Pariza. Synthetically prepared CLA isomers were applied topically to mice before inducing epidermal carcinomas. Mice that received topical CLAs developed only half the number of papillomas and exhibited a lower incidence of tumor formation relative to the control mice. Subsequent studies have shown that other murine carcinoma models show an improvement with CLA supplementation, including mammary, colon, stomach, prostate, and hepatic carcinomas.
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However, some studies have shown that CLA has no effect on tumor inhibition, and a few have even shown that CLA promotes tumor progression. Wong et al. did not find an effect of mixed CLA (up to 0.9%) supplementation on established aggressive mammary tumors in mice. Similarly, a higher dose of mixed CLA (3%) did not reduce the tumor burden in APCMin/+ mice, a genetic model that spontaneously develops intestinal tumors. A pilot study in mice suggested that mixed CLA supplementation increased tumor progression in PyMT transgenic mice, a mouse model of invasive breast cancer, and 10,12 CLA specifically has been shown to increase tumorigenesis in transgenic mice overexpressing ErbB2 in mammary epithelium, another murine model of mammary carcinoma.
While a handful of studies suggest that CLA has no effect on, or even worsens tumor progression, the majority of studies show beneficial effects of CLA supplementation. It is likely that the timing of the CLA supplementation is critical, and that CLA is most effective as an anti-carcinogen when administered during early tumorigenesis, and is less effective in models of established tumors.
Human Studies on Cancer
There is some evidence to suggest that CLA consumption reduces the incidence and progression of some types of cancer in humans. There is a significant negative correlation between milk intake and risk of breast or colon cancer, an effect that is coincident with elevated serum CLA levels in a particular group of Finnish women. Similarly, another study showed that subjects consuming four or more servings of dairy per day showed a reduced risk of colorectal cancer. Furthermore, a study was conducted in women with Stage I-III breast cancer, in which the subjects (n = 23, no placebo group) were given 7.5 g/day mixed CLA for at least 10 days prior to their tumor removal surgery. Spot 14 (S14), a regulator of fatty acid synthesis that has been shown to augment breast cancer proliferation, was decreased following CLA supplementation. Similarly, the Ki-67 scores declined with CLA treatment, indicative of a reduction in tumor proliferation.
However, additional studies performed by different groups on different cohorts of French and American women failed to show any correlation between CLA and incidence of breast cancer. Thus, with mixed results and a low number of studies, there is insufficient evidence to determine whether CLA ingestion has a significant effect on cancer.
Anti-Obesogenic Effects
Approximately 15% of adults in the United States report using non-prescription dietary supplements to promote weight loss, contributing to the billion-dollar nutraceutical industry that is not heavily regulated by the FDA. As such, the consumers of dietary supplements are at risk of side effects, variable efficacy, and adverse interactions with medications that may not be rigorously tested for nor acknowledged by nutraceutical manufacturers. With purported health benefits such as the promotion of weight loss, CLA has been marketed as a supplement to promote weight loss. CLA supplements are mass-produced synthetically from safflower oil and are encapsulated, and are readily available for purchase from many sources. Given that CLA supplements contain an equal proportion of 9,11 CLA and 10,12 CLA, the effects of CLA supplementation on body energetics can be dramatically different than the effects of CLA procured from the natural diet.
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The dramatic effect CLA has on adiposity has been studied for the past 20 years. Initial studies in male and female ICR mice showed that a mixed CLA (0.5% w/w)-supplemented chow diet promoted fat loss by 60% over 30 days, attributed to increased lipolysis and fat oxidation. Similarly, an early study in Sprague-Dawley rats noted that the triglyceride and non-esterified fatty acid levels were reduced in white adipose tissue in a dose-dependent manner, following three weeks of mixed CLA feeding. Importantly, both of these initial observations were made before there was an observable change in body weight. It was later determined that the active CLA isomer responsible for reducing adiposity was 10,12 CLA. The initial adiposity-lowering effect of mixed CLA has been confirmed many times in various mouse models, rats, hamsters, and pigs.
However, it is likely that CLA supplementation impacts distinct species, such as mice and rats, differently. Lean Zucker rats fed a 0.5% mixed CLA-containing diet for five weeks showed a reduced adiposity, while obese Zucker rats showed an enhanced adiposity. Much work has been devoted to understanding the mechanism(s) by which 10,12 CLA promotes fat loss in rodent models. Early studies suggested that 10,12 CLA promotes the oxidation of fat stores, assessed by measuring the gene expression of peroxisome proliferation activated receptor alpha (Ppara), and its downstream targets acyl coenzyme A oxidase (Acox1) and carnitine palmitoyl transferase-1 (Cpt1). Recent work has expanded on this observation, showing that 10,12 CLA robustly increases the conversion of radiolabeled fatty acids, such as palmitate and oleate, into carbon dioxide in cultured adipocytes, suggestive of enhanced fatty acid oxidation. Moreover, it has also been shown in vivo that acylcarnitines, major byproducts of fatty acid oxidation, are robustly increased in mice receiving 10,12 CLA supplementation.
More recent evidence points towards the browning of white adipose tissue as a mechanism of fat mobilization, to promote weight and fat loss. The first study to suggest that CLA (1.5% mixed isomer) promoted UCP1 expression in white adipose tissue was performed in ob/ob mice, a mouse model of spontaneous obesity due to the deletion of the leptin gene. Importantly, this study only reported white adipose tissue browning in epididymal (visceral) white adipose tissue, and this effect of CLA was noted during the obesogenic period. The next group to examine the browning effect of CLA in detail used Sv129 mice given low-doses of CLA isomers. This group showed that several low doses of 10,12 CLA (0.03%, 0.1%, and 0.3%) promoted the increased uncoupling protein 1 (UCP1) expression from both inguinal (subcutaneous) and epididymal (visceral) white adipose tissue in lean mice. This group went on to show that 10,12 CLA at the 0.1% dose could similarly promote white adipose tissue browning during low-fat diet feeding. In the study by Shen et al., 10,12 CLA was given at a dose that was approximately six-fold lower than the study by Wendel et al., yet promoted the browning of both epididymal (visceral) and inguinal (subcutaneous) white adipose tissue with minimal detrimental effects on liver weight. More recently, it has been shown that in a mouse model with phenotypes resembling human metabolic syndrome (Ldlr−/− mice fed a diet high in sucrose and saturated fat), 10,12 CLA (1%) promotes the substantial browning of white adipose tissue in obese mice, with coincidently increased energy expenditure. The mice were also able to better maintain a core body temperature when challenged with exposure to the cold, suggesting that the browning of white adipose tissue could be involved with thermogenesis.
Several groups have shown that CLA supplementation reduces the circulating levels of adiponectin, a hormone secreted from adipocytes that has anti-inflammatory, anti-atherogenic, and anti-diabetic properties. Recently, it has become recognized that while CLA supplementation reduces fat stores, it also dramatically decreases the circulating adiponectin levels in mice, which could explain why CLA-mediated weight loss is associated with impaired glucose metabolism. The reason for this loss of adiponectin is unclear, but a recent study suggests that by at least partially restoring the adiponectin levels, co-treatment with the thiazolidinedione rosiglitazone, a peroxisome proliferator activated receptor gamma (Pparg) agonist, can improve the metabolic outcomes associated with CLA supplementation.
CLA for Weight Loss: Human Studies and Considerations
While animal studies investigating CLA for weight loss indicate potential value, human studies have not yet replicated these results. Additionally, some animal research suggests CLA may cause inflammation and increased fat in the liver. It is important to note that some people claim that conjugated linoleic acid (CLA), a type of fatty acid, can be taken as a supplement to aid weight loss. However, human studies have not proved its efficacy or safety.
According to a 2017 study on mice, CLA supplementation can reduce weight, but it does not do this in an ideal way. The weight loss is largely due to a reduction of subcutaneous fat instead of visceral fat. Subcutaneous fat lies underneath the skin, while visceral fat lies around internal organs in the belly. Visceral fat causes more risks and can have negative health consequences. It is also linked to a higher death rate, as outlined in a 2022 research review. The authors of the study concluded that CLA-related weight loss is less metabolically healthy than other weight loss methods, such as calorie restriction.
Research notes that unlike animal studies on CLA, which suggest a dramatic weight loss effect, human studies are not promising or considerable. Studies involving humans have not proved the safety and efficacy of CLA. A 2019 meta-analysis on the effects of CLA on body composition suggests that CLA side effects include nausea, stomachache, diarrhea, bloating, headaches, and skin rashes. However, some people may tolerate it well. Additionally, weight loss from CLA does not link to improved glucose metabolism like weight loss from calorie restriction. It is instead associated with insulin resistance, a condition where cells do not respond adequately to insulin and cannot easily take up glucose from the blood. A 2022 meta-analysis suggests that CLA increased triglycerides, total cholesterol, and LDL but also increased HDL.
Dosage and Food Sources
A 2019 literature review looked over research to date on CLA. It included trials using doses ranging from 1.5 to 6.8 grams (g) per day. It found that doses higher than 3.4 g a day were more likely to reduce body weight than lower doses. However, because research on safety and effectiveness is lacking, a safer option would involve eating foods that are naturally enriched with CLA. CLA sources include milk and milk products such as cheese and yogurt. Certain types of meat also contain CLA, including lamb and beef.
Studies suggest that CLA has only modest effects on weight loss. Although it doesn’t cause any serious side effects at doses up to 6 grams per day, there may be long-term risks from higher doses. Most studies on CLA have used doses of 3.2-6.4 grams per day. One review concluded that a minimum of 3 grams daily is necessary for weight loss. Doses of up to 6 grams per day are considered safe, with no reports of serious adverse side effects in people. The FDA allows CLA to be added to foods and gives it a GRAS (generally regarded as safe) status. However, bear in mind that the risk of side effects increases as your dosage increases.
Potential Risks and Side Effects
The CLA found in most supplements is different from the CLA found naturally in foods. Several animal studies have observed harmful side effects from CLA, such as increased liver fat. Large doses of supplemental CLA can cause increased accumulation of fat in your liver, which is a stepping stone towards metabolic syndrome and diabetes. Numerous studies in both animals and humans reveal that CLA can drive inflammation, cause insulin resistance, and lower “good” HDL cholesterol.
However, some human studies using reasonable doses indicate that CLA supplements may cause several mild or moderate side effects, including diarrhea, insulin resistance, and oxidative stress.
When taken by mouth, CLA is likely safe when taken in amounts normally found in foods, such as milk and beef. It is possibly safe when taken in larger amounts as medicine. It might cause side effects such as stomach upset, diarrhea, nausea, fatigue, and headache.
Special precautions include avoiding use during pregnancy and breast-feeding due to a lack of reliable safety information. CLA supplements might slow blood clotting, potentially increasing the risk of bruising and bleeding in people with bleeding disorders. There are concerns that taking CLA supplements can worsen diabetes or increase the risk of getting diabetes if you have metabolic syndrome. CLA supplements might cause extra bleeding during and after surgery, so it's recommended to stop using it at least 2 weeks before a scheduled surgery.
CLA and Muscle Mass
While reducing fat, CLA helps increase lean muscle mass by reducing insulin sensitivity, which allows glucose and fatty acids to easily funnel into muscle cells as opposed to fat cells. It is recommended that you take one capsule of CLA with each meal. CLA is ideal for men and women looking to lose weight and reduce fat mass or those in a cutting phase who are focusing on getting lean and dropping weight without losing muscle mass. CLA is not suitable for vegetarians.