Download Brief Review Conjugated Linoleic Acid (CLA)

International Journal of Applied Research in Natural Products
Vol. 4 (3), pp. 12-18, Sep-Oct 2011
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Brief Review
Conjugated Linoleic Acid (CLA)-An Overview
Crumb DJ
Biology, Nutrition and Foods, Texas State University, Marcos, Texas 78666
Summary: Conjugated linoleic acid (CLA) is a group of octadecadienoic acids that are naturally present in the highest
concentrations in foods originating in ruminant animals, and dairy products such as milk. Especially large numbers of CLA
polymers have been detected in beef, lamb and milk fat. Results from many in vitro and animal studies, though conflicting, have
suggested that CLA supplementation may have beneficial effect on obesity, weight management, cancer, diabetes and
atherosclerosis. This article provides a brief overview on the functionality, safety and toxicity of CLA as described in literature. .
Industrial Relevance: CLA is a functional food and dietary supplement ingredient with potential benefits against a number of
metabolic chronic diseases. However, the mechanism of action and its toxicological effects are not very well understood. These
factors may play an important role in the effectiveness as CLA as a viable functional dietary bioactive compound.
Keywords: Conjugated linoleic acid; CLA; 9,12-cis-octadecadienoic acid
Introduction:
Conjugated linoleic acid (CLA) is a term used for a large group of positional and geometric isomers of linoleic
acid. Linoleic acid is an 18 carbon unsaturated, essential, dietary fatty acid (Steinhart 1996). Dietary sources for
linoleic acid include the oils of vegetables, seeds, and nuts (Kelly et al., 1997). The systematic name, 9,12-cisoctadecadienoic acid, indicates the position (C9 and C12) and geometry (cis) of the double bonds in this molecule.
Linoleic acid is converted to numerous CLA isomers in ruminant animals via the activity of a variety of bacteria and
enzymes located in the rumen and tissues. CLA isomers have conjugated unsaturated cis and/or trans double bonds
in various positions along the carbon chain. The isomers containing a trans double bond are biologically active, and
the c-9, t-11 and t-10, c-12 CLA isomers are of primary physiological importance (Khanal and Dhiman 2004; Mir et
al., 2004). Research related to CLA has revealed many promising health benefits for humans. The primary dietary
sources of CLA for humans are food products derived from ruminant animals, mostly cattle, including meat fat,
milk, cheese, yoghurt, and butter (Moon et. al., 2008). Many in vitro, in vivo, and animal studies indicate that CLA
could have beneficial effects as an anti-mutagen, antioxidant, and anti-carcinogen. Furthermore, it has been shown
to reduce LDL cholesterol and heart disease, modulate immune and inflammatory responses, and modulate lipid
metabolism (Steinhart 1996; Ferramosca et al., 2006).
Biosynthesis of Conjugated Linoleic Acid:
There are two biosynthetic processes responsible for the formation of CLA. These processes are carried out
primarily in ruminant animals, but also to a lesser extent in non-ruminant animals (Khanal and Dhiman 2004). The
first process is the incomplete biohydrogenation of linoleic acid and linolenic acid in the rumen (Bauman et al.,
1999). The second biosynthetic process is the endogenous conversion of transvaccenic acid, an intermediate of
biohydrogenation, to CLA in tissues (Bauman et al., 1999). The main dietary source of linoleic acid for ruminant
animals is concentrated feed consisting mainly of grains and seed oils, whereas the main dietary source of linolenic
acid is pasture grasses (Khanal and Olson 2004).
Biohydrogenation: Complete biohydrogenation of linoleic acid and linolenic acid results in the formation of steric
acid (C18:0), a saturated fatty acid (Khanal and Dhiman 2004). This conversion involves a three step biochemical
process mediated by two classes of bacteria, A and B, and by several enzymes. Biohydrogenation of linoleic acid
(c-9, c-12 C18:2) begins as group A bacteria isomerizes the c-12 double bond to t-11 to form the c-9, t-11 CLA
isomer. The next step is the reduction of the c-9 double bond by group A bacteria to form transvaccenic acid (t-11
C18:1). The final step utilizes group B bacteria to further hydrogenate the t-11 bond, thus converting transvaccenic
acid (t-11 C18:1) to steric acid (C18:0) (Bauman et al., 2003). This series of reactions is carried in the rumen at a pH of
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Conjugated Linoleic Acid
6.0 with the enzyme linoleate isomerase which is highly sterospecific for c-9, c-12 diene molecules (Khanal and
Dhiman 2004).
The biohydrogenation of linolenic acid (c-9, c-12, c-15, C18:3) follows a similar process of isomerization at c-12 to
form c-9, t-11, c-15 C18:3 followed by the reduction of the double bonds at c-9 and c-15 to yield transvaccenic acid.
Finally, the reduction of the t-11 bond forms steric acid (Khanal and Dhiman 2004). This process utilizes the same
bacteria and enzymes mentioned above for linoleic acid.
Abnormal physiological conditions in the rumen lead to the formation of the t-10, c-12 CLA isomer from linoleic
acid which is formed by a similar pathway but mediated by different bacteria and enzymes. The enzyme c-9, t-10
isomerase forms t-10, c-12 CLA in the first biochemical reaction and c-12, t-11 isomerase forms t-10 C18:1 in the
next reaction. The final reaction is the reduction of the t-10 bond to form steric acid (Khanal and Dhiman 2004).
Analysis of milk and tissue fats from ruminant animals reveals that c-9, t-11 CLA comprises 80-90% of total CLA,
whereas t-10, c-12 CLA comprises 5% or less of total CLA (Khanal and Olson 2004).
Overall, under normal conditions these biosynthetic pathways result in the formation of two biologically important
intermediates, c-9, t-11 CLA and transvaccenic acid. The rate of the biohydrogenation process is mediated by the
activity of group A and group B bacteria which are classified based on their metabolic pathways and end products.
Group A bacteria are far more abundant than group B bacteria in the rumen. Thus, excess Group A end products, c9, t-11 CLA and transvaccenic acid, remain in the rumen due to the lack of sufficient levels of Group B bacteria to
complete the biohydrogenation process (Bauman et al., 2003, Moon et. al., 2008). Furthermore, the reduction of
transvaccenic acid to steric acid by group B bacteria occurs slowly. These two properties of Group A and Group B
bacteria allow high concentrations of c-9, t-11 CLA and transvaccenic acid to accumulate in the rumen and
subsequently be absorbed into animal tissues (Bauman et al., 1999). However, the CLA synthesized via
biohydrogenation accounts for only 10-15% of the total CLA in ruminant food products (Khanal and Dhiman 2004).
Endogenous Conversion: The second biosynthetic pathway for the formation of CLA is an endogenous process
that converts transvaccenic acid to CLA in the tissues and fat of ruminant animals. In this process, the enzyme ∆9desaturase in conjunction with several other enzymes, specifically introduce a c-9 double bond into the
transvaccenic acid formed as an intermediate of the biohydrogenation process of linoleic acid and linolenic acid in
the rumen as described above. The addition of the c-9 double bond into transvaccenic acid yields c-9,t-11 CLA
(Khanal and Dhiman, 2004). The ∆9-desaturase enzyme is found primarily in the adipose tissue of beef cattle and in
the mammary gland of lactating dairy cattle (Bauman et al., 1999). This biosynthetic process accounts for 60-90%
of the total CLA content in ruminant food products (Khanal and Dhiman, 2004).
CLA Concentration in Animal Food Products:
The history of CLA dates back to the 1930’s when conjugated fatty acids were first identified in the milk of
grazing cattle. Booth et al. (1935) performed spectroscopic fatty acid analysis on butter fat from the milk of grain
fed cattle in the winter and pasture fed cattle in the summer. They determined that the fatty acid concentration
nearly doubled in the butter produced from summer cattle and attributed the increase to a modified form of linoleic
acid (Booth et al., 1935). It was not until 1977 that this modified form was identified as the c-9, t-11 CLA isomer
(Khanal and Dhiman 2004). In addition, research at the University of Wisconsin in the late 1970’s serendipitously
found an anti-mutagenic molecule in raw and cooked beef and identified it as an isomer of CLA (Steinhart 1996).
As a result of this discovery, research on CLA has markedly increased over the last three decades and possible
health benefits for humans continue to immerge.
One area of research has focused on methods to increase the concentration of CLA in animal food products meant
for human consumption. Studies have shown that under normal physiological conditions CLA accounts for only
0.2% to 2.0% of total ruminant milk or tissue fat and that milk fat has a much higher concentration of CLA than
tissue fat (Khanal and Olson 2004). For humans, the recommended therapeutic daily intake of CLA ranges from 1.5
to 3.5 g/day while CLA concentrations in beef range from 1.2 to 12.5 mg/g of fat (Mir et al., 2004; Zlatanos et al.,
2008). Thus, to obtain the lowest recommended daily intake of CLA, one would have to eat a minimum of 120g of
beef fat per day. Several factors affecting CLA concentration have been identified and this knowledge has been
used in an effort to increase the overall CLA concentration in animal food products consumed by humans.
Fatty acid analysis of the milk and meat of ruminants raised under the same physical and environmental conditions
have revealed variations in the CLA content among these animals. Causative factors for this variation can be
explained as diet, post-harvest processing, and individual animal differences (Khanal and Olson 2004). Research
has shown that dietary factors tend to have the greatest overall effect on CLA content in both milk and meat fat.
Numerous studies, including the one by Booth et al. mentioned previously, have shown that cattle turned out to
pasture in the summer months show a two to three-fold increase in CLA concentration (Khanal and Olson 2004).
However, other methods to increase concentration are necessary for feedlot cattle on a diet of total mixed rations
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Crumb D, Vattem DA
consisting of 50% forage and 50% concentrate (Chouinard et al., 2001; Khanal and Olson, 2004). Lipid
supplements of animal origin have traditionally been added to cattle feed to increase the energy density of milk and
meat. Recently, various forms and preparations of plant based lipid supplements have been studied to determine
their effect on CLA levels (Chouinard et al., 2001). However, lipid supplements of plant origin are known to cause
a decrease in milk fat content. The goal of lipid supplement manipulation is to increase the availability of linoleic
and linolenic acids in the rumen for biohydrogenation and endogenous synthesis of CLA while maintaining normal
levels of milk fat (Khanal and Olson 2004).
The seeds and oils of numerous vegetables, seeds, and nuts are rich sources of linoleic acid, linolenic acid, and
oleic acid, all of which have been shown to increase CLA concentrations in milk fat. Soybean and sunflower oils
yield the greatest increase under standard conditions and when added to the finishing diet of cattle can increase the
meat fat CLA concentration by 75% (Khanal and Olson 2004; Mir et al., 2004). A study by Chouinard et al. (2001)
tested various preparations of soybeans and their effects on overall milk yield, milk fat content, and CLA
concentration. In this study heat treatment followed by additional processing of soybeans increased the availability
of the linoleic acid rich oils. Increasing the bioavailability of the oil increased the CLA concentration in milk from 4
mg/g of fatty acid to over 20 mg/g of fatty acid without decreasing total milk fat content (Chouinard et al., 2001).
Furthermore, linoleic acid supplementation from soybean, sunflower, safflower, solin, and cottonseed is more
effective in increasing CLA concentrations than linolenic acid supplementation from linseed. This is most likely
due to the fact that biohydrogenation of linoleic acid produces both CLA and transvaccenic acid intermediates,
whereas linolenic acid only produces the transvaccenic acid intermediate. Addition of fish oil to linoleic and
linolenic acid supplements has been shown to further increases CLA concentrations from 6mg/g of fatty acid to
18mg/g of fatty acid (Chouinard et al., 2001; Khanal and Olson 2004).
There are a variety of factors that can affect the normal physiological conditions of the rumen. Low forage diets
can lower the pH and alter the bacterial content of the rumen creating and adverse environment for the
biohydrogenation of linoleic and linolenic acids (Khanal and Olson 2004). Thus, methods to decrease the
metabolism of lipid supplements by rumen bacteria are another important area of research. One of the most
effective methods for ruminal protection of CLA is the creation of calcium salts of fatty acids which protect them
from bacterial degradation. Calcium salts of fatty acids from soybean oil increased the CLA concentration of milk
fat from 4 mg/g of fatty acid to 23 mg/g of fatty acid (Chouinard et al., 2001; Moon et al., 2008). In addition, green
tea catechins are known for their antioxidant and free radical scavenging activity. Thus, the addition of green tea
extracts to cattle feed has been shown to reduce CLA oxidation in the rumen (Moon et al., 2008).
In addition, several studies have been performed on increasing the CLA concentration in fish. Fish are important
sources of protein and polyunsaturated fatty acids for humans and increasing their CLA levels could increase their
nutritional value (Zhao et al., 2008). Studies on large yellow croaker, yellow perch, tilapia, bass, salmon, and many
other fish have indicated that seed oil supplementation can increase the CLA content of muscle tissue without
affecting growth rate and feed efficiency (Twibell et al., 2001, Zhao et al., 2008). However, there is evidence that
supplementation should be species specific due to specificity for dietary essential fatty acids among species (Twibell
et al., 2001).
Consumer response is an important consideration in evaluating the success of CLA enhanced products. Several
surveys and studies have shown that overall consumer reaction has been positive. A survey of consumers testing
milk with increased levels CLA showed that they found no difference in acceptability and some were willing to pay
more for the enhanced product (Ramaswamy et al., 2001). Furthermore, meat with increased CLA concentration
received better retail acceptability scores than the control meat, and the tenderness and palatability scores of the
enhanced CLA meat were not affected (Mir et al., 2004). However, increasing the CLA concentration in the diet of
laying hens changed the fatty acid composition of the eggs produced which led to undesirable color changes in the
yolk and albumen (Aydin 2006).
CLA and Disease:
Over the last three decades, extensive research has been conducted concerning CLA and its possible health
benefits for humans including weight management, cancer prevention, reduction and prevention of atherosclerosis,
and immune system modulation. One of the first benefits of CLA was discovered in 1977 as Pariza and his colleges
were isolating known mutagens and carcinogens in cooked beef and discovered an unexpected anti-mutagenic
compound. They continued research on this unknown, unidentified compound and found that it reduced papilloma
incidence in mouse models. Two years later, the compound was identified as a mixture of CLA isomers
(Kritchevsky 1999). Since that time, extensive research has been performed to determine the extent of CLA’s health
benefits in animals and humans as well as the mechanism of action through which CLA mediates this processes.
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Conjugated Linoleic Acid
Cancer: Research has found that CLA can be effective in inhibiting initiation, promotion, and progression of
breast, colon, skin, and prostate cancers (Field and Schley 2004). A considerable amount of research has been
dedicated to the effects of CLA on various breast cancer cell lines. Breast cancer is the most prevalent cancer
among women in developing countries (Aro et al., 2000). As mentioned previously, the primary natural source of
CLA is the food products of ruminant animals. Thus, determining the efficacy of CLA as a treatment for breast
cancer could have a major impact on the health of these developing populations. Numerous studies have reported a
decrease in tumor formation and growth with CLA supplementation in animals and humans. Rat studies have
indicated that CLA supplementation during mammary development reduces the risk of mammary tumor
development and that long term protection can be achieved through long term supplementation (McGuire and
McGuire 1999).
In humans, 75% of breast cancers are estrogen receptor α (ERα) positive, meaning that estrogen enhances the
growth and proliferation of breast cancer cells. However, at a daily therapeutic dose of 10-80µm, CLA has been
shown to inhibit estrogen stimulated cell growth possibly by regulation of estrogen receptor expression.
Furthermore, CLA can induce apoptosis of ERα(+) MCF-7 cell lines. These anti-estrogenic effects of CLA are most
likely attributed to decreased expression of Bcl-2, an anti-apoptotic protein which increases it expression with
increased estrogen (Wang et al., 2008).
The indirect pro-oxidant properties of CLA have been studied as another possible mechanism for CLA’s
anticarcinogenic effects. Cell culture studies have indicated that following the addition of CLA to a medium with
cancer cells, CLA is directly incorporated into the cancer cell membrane to an extent proportional to the
concentration of CLA added. This alteration of the cell membrane induces lipid peroxidation which ultimately alters
the biophysical properties and cell signaling pathways of the membrane. This is thought to lead to a cytotoxic
cascade which inhibits the growth and proliferation of the cancer cells (Devery et al., 2001).
The majority of the studies in humans have tested the effect of dairy product consumption on cancer risk.
Although some have found an inverse relationship between dairy consumption and cancer risk, it is impossible to
determine if the effects observed are related to CLA, other fatty acids, or other variables such as folate, vitamin B-6,
and fiber which also increase with increased dairy consumption (Larsson et al., 2005). On the other hand, animal
studies have directly tested CLA and tumor growth both in vitro and in vivo and have shown a more definitive
inverse correlation. Thus, CLA must be a considered factor in the dairy studies mentioned (Aro 2008).
Obesity: The effect of CLA on overall body composition is one of the most documented fields of CLA research.
This is probably due to the fact that obesity is a major risk factor for many of the other conditions studied in
conjunction with CLA such as atherosclerosis and diabetes. CLA has been available in supplement form and is
promoted as a weight loss supplement (Larsen et al., 2006). Most research has supported the efficacy of
supplemental CLA for weight loss. Animal studies on mice, rats, and hamsters have shown an alteration in overall
body composition following CLA supplementation (Gaullier et al., 2004). One human study of middle aged men
found a significant decreasing in abdominal fat but no change in the body mass index (BMI) (Riserus et al., 2000).
In addition, a long term study indicated a significant decrease in body fat mass after 12 months of CLA
supplementation and a recent meta-analysis indicated that CLA is beneficial in reducing body fat mass (Larsen et al.,
2006; Nakamura et al., 2008). However, no beneficial effects related to the prevention of weight gain have been
documented (Larsen et al., 2006). Overall, the mechanism through which CLA induces body mass loss is not well
understood and doubt remains as to the efficacy of CLA supplementation for humans. Because obesity leads to
atherosclerosis and diabetes, the effects of CLA on these diseases is often studied in conjunction with obesity. The
results of these studies tend to be similar to the results of studies done on average weight subjects. Thus, the
mechanisms of action are probably independent of each other.
Atherosclerosis: Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaque in
arteries. Plaque formation begins as low-density lipoprotein (LDL) cholesterol is oxidized in the artery and engulfed
by macrophages which, in turn, produce foam cells that leads to fatty streaks on the wall of the artery. These fatty
streaks accumulate and are hardened to plaque by mineral deposition. Eventually, this plaque stiffens and narrows
the artery. In response to plaque formation, blood clots form and stick to the artery wall. These clots can break free
and occlude smaller arteries where they inhibit blood flow to the tissues (Nakamura et al., 2008).
To date, most animal and human studies on the effects of CLA on atherosclerosis have been inconclusive and
contradictory. Several studies have indicated a decrease in LDL, total cholesterol, triglyceride, and fat deposition
levels with CLA supplementation, while other studies indicate an increase in HDL with an increase in fatty streak
development (McGuire and McGuire 2000). The results of human studies have been similarly inconclusive. A
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Crumb D, Vattem DA
meta-analysis determined that the therapeutic efficacy of CLA as a treatment for atherosclerosis cannot be
determined at this time (Nakamura et al., 2008).
Research to determine a possible mechanism of action has revealed a wealth of knowledge related to CLA on a
molecular level. Most of this research has focused on atherosclerosis as an inflammatory condition. It has been
proposed that CLA can mediate inflammatory gene expression, thus altering the signaling pathway that leads to the
formation of reactive oxygen species (ROS). ROS not only oxidize LDL, but also negatively affect the vascular
endothelium. Furthermore, CLA alters the metabolism essential fatty acids such as linoleic acid which synthesizes
arachidonic acid by elongation and desaturation. CLA inhibits the synthesis of arachidonic acid and thus modulates
the inflammatory response which is generally under the control of eicosanoids produced by arachidonic acid
(Nakamura et al., 2008). Continuing research on gene expression, fatty acid metabolism, and immune and
inflammatory responses will ultimately help determine the efficacy of CLA as a prevention and treatment method
for atherosclerosis.
Diabetes: Type 2 diabetes is a metabolic disorder characterized by insulin resistance, hypertension, dyslipidemia,
microalbuminuria, and low grade inflammation (Moloney et al., 2004). The effects of CLA on insulin levels are
noted as a possible adverse effect in a considerable amount of the research related to obesity, atherosclerosis, and
cancer. In particular, visceral fat deposits have been shown to be highly sensitive to CLA, exhibiting rapid decrease
in fat accumulation followed by a proportional increase in fasting insulin levels (Riserus et al., 2001). Thus, further
research conducted to determine the overall effect of CLA on type 2 diabetes has shown that CLA’s possible
therapeutic effects are related to insulin resistance and hyperlipidemia (Moloney et al., 2004).
Research indicates that there is a strong isomer dependent relationship with regards to the effects of CLA on
various diabetic parameters, with the c-9, t-11 isomer having the most positive effects. However, a study by
Moloney et al. (2004) indicates that there is not a positive correlation between CLA intake and insulin and glucose
concentrations. With regards to the other parameters of the metabolic syndrome, CLA was shown to reduce the risk
of cardiovascular disease. However, the overall conclusion of this study is that CLA supplementation is not an
effective strategy in the management of type 2 diabetes (Moloney et al., 2004).
Immune Response Modulation: The effects of CLA in the modulation immune responses have several positive
implications for human health. CLA has been shown to modulate the production eicosanoids, prostaglandins,
cytokines, and immunoglobulins. Specifically, CLA reduces the concentration of immunoglobulin E (IgE) and thus
reduces allergic reactions (O’Shea et al., 2004). CLA has been shown effect immune defenses in three ways. First,
CLA improves T-cell function, thus increasing lymphocyte proliferation and increasing the overall effectiveness of
the adaptive immune system to antigen-specific responses. Next, it increases humoral function by increasing
production of IgA which is produced in response to complex blood borne pathogens and allergens. Finally, CLA
mediates macrophage function by reducing anti-inflammatory responses (Field and Schley 2004; O’Shea et al.,
2004). Furthermore, CLA has been shown to alter eicosanoid production by incorporating arachidonic acid into the
cell membrane and altering its signaling pathways (O’Shea et al., 2004). Overall, CLA modulates allergic and
infectious immune responses by different pathways and different mechanisms of action.
Safety and Toxicity:
The safety of CLA supplementation is generally a large part of the analysis CLA effectiveness in reducing and
preventing disease. Studies on the safety of CLA supplementation are generally performed on animal models.
These animals are tested with doses much higher than would be used in therapeutic treatment in humans. Most of
these studies have determined that CLA supplementation is safe (Pariza 2004). Human trials on the safety and
efficacy of CLA supplementation have also been conducted using high quality, controlled levels of CLA. These
studies also concluded that at therapeutic doses, there are few adverse effects (Pariza 2004). Common adverse
effects in humans include changes in insulin sensitivity, changes in the LDL to HDL ratio, and gastrointestinal upset
(Larsen et al., 2006). However, questions have been raised about more serious safety issues concerning CLA
supplementation in humans including increased fatty deposits in the liver, insulin resistance, and lipodystrophy.
Fat accumulation in the liver and liver hypertrophy has been noted in mice and hamster research designed to
determine the safety of CLA supplementation. It has been noted that these two conditions are not considered to
show a toxic effect. However, a case report of a healthy adult human has attributed toxic hepatitis to CLA
supplementation. Similar to the effects seen in animal models, the hepatotoxic effects of CLA diminish as
supplementation is discontinued (Pariza 2004; Ramos et al., 2008). As noted above, insulin resistance varies on a
case and species basis. In addition, some studies indicate that the t-10, c-12 CLA isomer has a significant positive
effect on diabetic parameters including insulin resistance. However, the c-9, t-11 CLA isomer has been shown to
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have anti-diabetic effects (Moloney et al., 2004). Similarly, various animal studies have shown a wide range of
effects related to blood glucose levels, insulin sensitivity, and insulin resistance (Pariza 2004). Lipodystrophy is also
indicated in mouse models and is most likely associated with de novo fatty acid synthesis in mouse hepatocytes as
overall body fat is reduced. This effect has not been seen in any other species to date. Another possible toxic effect
of CLA is the alteration of the ratio of arachidonic acid to DHA. Arachidonic acid is synthesized form linoleic via
elongation and desaturation in humans. There is little research available on the mechanism and effect of this
alteration, but it is a field that needs to be researched due to its negative consequences.
Conclusion:
Conjugated linoleic isomers have demonstrated many beneficial and detrimental effects in human and animal
studies. The best studied effects relate to obesity, atherosclerosis, cancer, diabetes, and immune system modulation.
Although many animal studies have had overall positive results in many of these areas, human studies have been
much less conclusive. Furthermore, the safety and possible toxicity of CLA has yet to be definitively determined.
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