1315

Potential Health Benefits of Conjugated Linoleic Acid (CLA): A Review

R. C. Khanal*
Animal Nutrition Division, Nepal Agricultural Research Council, P.O. Box 1950, Kathmandu, Nepal
ABSTRACT : Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid with two
conjugated double bonds. Of more than a dozen isomers of CLA found naturally in dairy and meat products from ruminants, c-9, t-11
and t-10, c-12 are the two isomers with known physiological importance, including anticarcinogenic, antidiabetic, antilipogenic, and
antiatherosclerotic effects. Positive effects of CLA on immune function and bone modeling have also been reported. In spite of the
compelling findings in tissue cultures and experimental animal models, its effect, dose, and mechanism of action vis--vis specific
isomers remains speculative. Results obtained from animal models are inconclusive and conflicting at times in humans, where the
research data is limited. It appears that there is a long way to go before CLA could be accepted unequivocally as having definite effects
in any or all of these physiological states and how such effects actually occur in humans. The objective of this review is to critically
examine the available literature on potential health benefits of CLA observed in cell culture, animal models, and human subjects,
wherever possible and to a certain extent the mechanism of action associated with these biological activities. (Asian-Aust. J. Anim. Sci.
2004. Vol 17, No. 9 : 1315-1328)
Key Words : Conjugated Linoleic Acid, Potential Health Benefits, Animals, Humans

INTRODUCTION
Conjugated linoleic acid (CLA), found naturally in food
products from ruminants, refers to a mixture of positional
and geometric isomers of linoleic acid (c-9, c-12 C18:2) with
two conjugated double bonds at various carbon positions in
the fatty acid (FA) chain. Each double bond can be cis or
trans, but those with one trans double bond are bioactive
(Jensen, 2002). It is formed as an intermediate during the
biohydrogenation of linoleic acid to stearic acid in the
rumen by Butyrivibrio fibrisolvens (Kepler et al., 1966) and
other rumen bacteria (Kritchevsky, 2000) or from the
endogenous conversion of t-11 C18:1 (transvaccenic acid,
TVA), another intermediate of linoleic or linolenic acid
biohydrogenation, by 9-desaturase in the mammary gland
(Griinari and Bauman, 1999; Corl et al., 2001) and possibly
in adipose tissues (Gillis et al., 2003). Of the two
physiologically important isomers, c-9, t-11 is the most
prevalent one comprising 80 to 90% of total CLA in foods
from ruminants (Table 1), whereas t-10, c-12 isomer is
present in small amounts at 3 to 5% of the total. Another
isomer c-9, c-11 has been found even more potent that c-9,
t-11 or t-10 c-12 isomers against human breast cancer cells
recently (Tanmahasamut et al., 2004). However, its
presence in lipids from ruminants is rarely reported.
Although it is relatively easy to raise the concentration of c9, t-11 CLA in ruminant lipids primarily through
manipulation of animal diet, increase in t-10, c-12 isomer
content through manipulation of animal diet is nominal
(Khanal and Olson, 2004). Based on the dose required in
* Corresponding Author: R. C. Khanal. Tel: +977-1-5523039,
Fax: +977-1-5521197, E-mail: rameshkhanal@hotmail.com
Received May 7, 2004; Accepted May 19, 2004

animal models (Ip et al., 1999), such an approach would

help meet the dose shown to be effective to derive the
potential health benefits associated with c-9, t-11, but not t10, c-12 CLA.
Ever since Ha et al. (1987) demonstrated that CLA
obtained from fried ground beef inhibited carcinogenesis, a
whole new era of research dedicated to CLA has opened.
Initially the studies were related more to the
anticarcinogenic properties of CLA. Later its positive
effects on diabetes (Belury and Vanden Huevel, 1999),
atherosclerosis (Nicolisi et al., 1997), lipid metabolism
(Terpstra et al., 2002), bone modeling (Watkins and Seifert,
2000), immune response (Cook et al., 1999), and vitamin A
metabolism (Carta et el., 2002) have been demonstrated in
various experimental animal models. Although there have
been a few attempts at verifying the positive effects of CLA
in human health through case control studies, it is not yet
possible to clearly state that CLA supports all those benefits
in humans as well. Moreover, the mechanisms of action
through which CLA exerts its effects have been speculative
at best (Belury, 2002b; Pariza et al., 2003). Another
important question that has been raised but not answered is
the dose needed to bring about the desired effects vis--vis
the specific CLA isomers. Some of the reviews on the
subject have dealt the beneficial effects of CLA on these
physiological cases, e.g. cancer (Banni et al., 2003),
diabetes (Belury, 2003), lipid metabolism (Keim, 2003),
bone modeling (Watkins et al., 2003), immune response
(Cook et al., 2003) etc., separately in detail, though
sometime with a thinking that CLA could be beneficial in
everything related to obesity. The objective of this paper is
to provide a critical and comprehensive review on various
aspects of CLAs potential health benefits and the

R. C. KHANAL

1316
Table 1. The mean positional
(% of total isomers) and the
butter, cheese, and beef fat1
CLA isomer
cis, trans-isomers
7, 9
8, 10
9, 11
10, 12
11, 13
11, 13
12, 14
Total cis, trans (trans, cis)
Trans, trans isomers
6, 8
7, 9
8, 10
9, 11
10, 12
11, 13
12, 14
13, 15
Total trans, trans
Cis, cis isomers
8, 10
9, 11
10, 12
11, 13
Total cis, cis
Total CLA (% of fat)
1

and geometric isomer composition

CLA content of samples of milk,
Milk2

Butter Cheese

5.5
1.5
72.6
0.4
7.0
0.7
87.7

6.7
0.3
76.5
1.1
0.4
0.8
85.8

3.6
1.0
83.5
4.7
0.4
93.2

7.0
2.6
72.0
2.6
1.1
2.2
0.7
88.2

2.4
0.4
2.0
0.6
4.2
2.8
12.3

9.4

0.1
0.6
0.3
1.5
0.5
2.3
0.9
0.1
6.3

0.7
1.5
0.7
3.7
1.9
1.9
1.9
12.3

4.8
0.5

<0.1
0.3
<0.3
0.3
0.7
0.93

Beef

0.27

Adapted from Parodi (2003). 2 Shingfield et al. (2003).

mechanisms of action speculated thus far in a rather brief

form without having to make a case for CLA.
CLA and cancer
Fats in general have been implicated in many forms of
cancer, yet evidence is accumulating that certain types of
FA have anticancer properties, of which CLA is the major
one. Inhibitory effects of CLA against carcinogenesis have
been demonstrated in a variety of cell type, sites, and
animal models including mammary gland, skin, colon,
prostate, and forestomach of rats, humans, mice, and
hamsters. In contrast to the hundreds of phytochemicals
possessing varying degrees of anticancer properties
(Scimeca, 1999), CLA is unique in that it is a FA, is found
in highest amounts in food products derived from ruminants,
and is safe at dietary levels. It is believed that CLA is
involved in a variety of biological events in all three stages
of carcinogenesis viz initiation, promotion, and progression.
It is also believed that the effects vary with the specific
isomers of CLA and the type and site of the cell/organ as
well as the stage of tumerogenesis. Overall, the effects of
CLA are related to inhibition of growth and proliferation,
induction of apoptosis, and diminishing branching and
reducing the density of ductal system of the cancerous cells

(reviews by Kritchevsky, 2000; Parodi, 2001; Belury,

2002a). Some important and recent studies related to CLA
and cancer has been presented in Table 2. For further
reviews on the subject one is referred to Banni et al. (2003),
Pariza et al. (2003), Scimeca (1999), and various references
cited in Table 2. It should, however, be mentioned that none
of these effects have been verified by clinical studies in
humans.
It was found that mammary tumor mass (Lavillonniere
et al., 2003) and incidence and weight (Ip et al., 1991) was
reduced in rats fed CLA. Exposure to 1% CLA during the
early preweaning and pubertal period only was sufficient to
reduce the subsequent methylnitrosurea induced
tumerogenesis in rats (Ip et al., 1995). It may have further
implications in cancer prevention in humans once it is
proven with clinical case-control studies, because
preweaning and pubertal period are two different stages in
mammary development. Ip et al. (1999) also found that
CLA decreased mammary tumor incidence by 50% and
tumor number by 45% in rats fed CLA at 0.8% of the diet.
By way of comparison, the efficacy of fish oil, which is also
an anticancer agent and which is not plant derived, is 100
times lower than that of CLA (Scimeca, 1999). Hubbard et
al. (2000) showed that CLA was not only involved in
altering mammary tumor incidence, but also effect later
stages, especially metastasis as effectively as indomethacin,
a known suppressor of tumor growth and metastasis in
murine mammary tumors. It supports the notion that CLA
may be efficacious in preventing the development and
recurrence of some cancers as well as suppressing the
growth of residual disease. Moreover, effect of CLA as an
anticancer agent is same whether it is provided through high
CLA foods produced naturally or when it is supplied as
pure synthetic CLA isomers (Ip et al., 1999). For instance,
OShea et al. (2000) found that cell number was decreased
up to 90% and lipid peroxidation increased by 15 fold
following incubation of breast cancer cells for 8 days with
increasing levels of milk yielding CLA concentrations
between 16.9 and 22.6 ppm. Similarly, when human breast
cancer cells were cultured with CLA enriched milk, cell
number decreased to 61% of the original level (Miller et al.,
2003b). An important observation was that rats fed CLA
enriched butterfat accumulated more CLA in the mammary
gland and other tissues than did rats fed synthetic CLA
isomers (Ip et al., 1999). This led to a new hypothesis
(discussed later) that TVA in butter fat may serve as the
precursor for the endogenous synthesis of CLA by -9
desaturase. These observations are encouraging and provide
a venue for planning intervention strategies through diet. It
should be noted that synthetic CLA contains about a dozen
of isomers, c-9, t-11 and t-10, c-12 being the most abundant
ones at approximately 1:1 ratio, while that present in milk,
meat, or butter fat is primarily c-9, t-11 at 80 to 90% or

POTENTIAL HEALTH BENEFITS OF CLA

Table 2. Biological effects of CLA on carcinogenesis and diabetes
Study/model/cell line
Effects
A. Carcinogenesis
Human breast cancer cells1
Damage to carcinogenic DNA
Reduced cell number and gene expression
Caco-2 cells2
Suppression of COX-2 and NOS
Endotoxin-activated macrophage3
Rat mammary cancer cells4
33-36% reduction in number
Reduction in cell number and proliferation
DMBA and DMH treated rats5
Reduced invasion of SGC-7901 cells
Human SGC-7901 cell line6
No effect
Patients with localized breast cancer7
Human colon HT-29 cell line8
Reduced DNA and increased apoptosis
Weak, positive relation
Epidemiological (breast cancer)9
Blocked cell cycle, increased apoptosis
SGC-7901 cells in vitro10
Increased apoptotic cells, reduced tumor size
Mouse forestomach neoplasia11
Reduced carcinogen-DNA adduct formation
Several12
Reduced size and number
Rat mammary tumor13
-ve correlation with CLA and TVA
Human case-control (breast cancer) 14
Finnish breast cancer study15
Inverse relation with the intake of milk and dairy products
Reduced tumors and tumor mass
Women with breast cancer16
Decreased tumor yields
Mice17
B. Diabete
Decreased blood glucose, plasma leptin, body weight and body mass index
Human diabetics18
Improved glucose tolerance and glucose transport
Obese Zucker (fa/fa) rats19
Induced hyperinsulinemia and fatty liver
C57Bl/6J mice20
Improved glucose transport
Obese Zucker rat21
Obese men22
Increased insulin resistance and glycemia
Increased glucose transport, glycogen synthase, and glucose tolerance and
Zucker diabetic rats23
upregulated UCP2
Type 2 diabetic subjects24
Inverse relation with body weight and serum leptin

1317

Isomer*
a
b
d
a/b
d
a
a
d
d
a
a/b
d
a
d
d
c
b
b
b
a/b
b
b
b

* a=c-9, t-11, b=t-10, c-12, a/b=c-9, t-11 and t-10, c-12, c=mixture, d=not known.
1
Majumdar et al. (2002), 2 Kim et al. (2002a), 3 Iwakiri et al. (2002), 4 Ip et al. (2002), 5 Cheng et al. (2003), 6 Yang et al. (2003b), 7 Chajes et al. (2003),
8
Cho et al. (2003a), 9 Voorips et al. (2002), 10 Liu et al. (2002), 11 Chen et al. (2003), 12 Scimeca (1999), 13 Ip et al. (1999), 14 Aro et al. (2000), 15 Knekt and
Jrvinen (1999), 16 Lavillonniere and Bougnoux (1999), 17 Belury et al. (1996), 18 Belury et al. (2002), 19 Henriksen et al. (2003), 20 Clment et al. (2002),
21
Teachey et al. (2003), 22 Risrus et al. (2002), 23 Ryder et al. (2001), 24 Belury et al. (2003).

even more of the total CLA isomers.

Using the apoptotic marker YO-PRO(R)-1, Drouin et al.
(2004) showed that c-9, t-11 CLA was the best apoptotic
inducer compared with t-10, c-12 or a mixture of c-9, t-11
CLA and t-10, c-12 isomers both in MCF-7 and MDA-MB231 cells. This is in contrast to previous findings on
colorectal and prostate cancer cells where t-10, c-12 CLA
led to an apoptotic response (Miller et al., 2002; Palombo et
al., 2002). Moreover, c-9, t-11 CLA also turned out to be the
best radiosensitizer compared with t-10, c-12 or a mixture
of c-9, t-11 CLA and t-10, c-12 isomers (Drouin et al.,
2004). The radiosensitizing property of c-9, t-11 CLA
supports its potential as an agent to improve radiotherapy
against breast carcinoma and needs further research for its
use in humans.
At cytosolic concentrations, CLA elicited cell cycle
arrest in G1 and induced the accumulation of the tumor
suppressors p53, p27, and p21 protein, with t-10, c-12
isomer being more effective than c-9, t-11 isomer in
inhibiting cell proliferation of MCF-7 breast cancer cells
and enhancing the accumulation of p53 (Kemp et al., 2003).
It reduced serum and mammary gland vascular endothelial

growth factor (VEGF) and its receptor Flk-1 concentrations

(Masso-Welch, 2002; Ip et al., 2003). Both c-9, t-11 and t10, c-12 isomers inhibited functional vascularization of a
matrigel pellet in vivo and decreased serum VEGF
concentrations; the t-10, c-12 isomer also decreased the
proangiogenic hormone leptin (Masso-Welch et al., 2004).
Additionally, the t-10, c-12 isomer, but not c-9, t-11, rapidly
induced apoptosis of the white and brown adipocytes as
well as the preexisting supporting vasculature of the
mammary fat pad, with both isomers inducing a rapid and
reversible decrease in the diameter of the unilocular
adipocytes (Masso-Welch et al., 2004).
In rodents, CLA-induced reduction in colon cancer
incidents (Kim et al., 2002a) is probably through
mechanisms involving apoptosis (Cho et al., 2003a). After 4
days of incubation with pure c-9, t-11 CLA, t-10, c-12 CLA
and their mixture, CLA-treated colon SW 480 tumor cells
displayed an increase in the activity of caspase-3 (27-34%)
and caspase-9 (37-47%) (Miller et al., 2002), both of which
are associated with apoptosis. Similar results of caspasedependent apoptosis were observed in both colo-rectal and
prostate cancer cells Palombo et al. (2002), which were also

1318

R. C. KHANAL

time- and dose-dependent in Jurkat T cells (Bergamo et al.,

2004). In human colo-rectal cells, both c-9, t-11 and t-10, c12 CLA isomers induced dose-dependent inhibitory effects
on cancer proliferation in vitro (Palombo et al., 2002). In
human HT-29 colon cancer cell line, CLA inhibited cell
proliferation and stimulated apoptosis in a dose-dependent
manner by downregulating mRNA and protein levels of
ErbB2 and ErbB3, both of which are implicated in the
development of colon cancer (Cho et al., 2003b). In another
study, c-9, t-11 CLA fed rats inhibited the development of
aberrant crypts, also called preneoplastic lesions in colon
cancer (Nichenametla et al., 2004), while t-10, c-12 CLA
inhibited HT-29 cell growth through reduced IGF-II
secretion (Cho et al., 2003b). In Caco-2 cell line, inhibition
of growth by CLA has been proposed to be due in part to
increased oleamide production (Kim et al., 2002a).
In human gastric carcinoma cell line, CLA inhibited the
cell proliferation, cellular mitosis, cell clone formation and
DNA synthesis, and induced cellular differentiation of
SGC-7901 cells (Liu et al., 1999). In another study, c-9, t-11
CLA suppressed reconstituted basement membrane invasion
of gastric carcinoma cell line SGC-7901 (Yang et al.,
2003b). The growth and proliferation of SGC-7901 cells
were inhibited by c-9, t-11 CLA via blocking the cell cycle
and expression of bcl-2 pathways associated with
mitochondria (Liu et al., 2002). In mouse forestomach
neoplasia, both c-9, t-11 and t-10, c-12 isomers showed
inhibited carcinogenesis in terms of the incidence and size
of the tumor, mechanism for which was suggested to be
complicated (Chen et al., 2003). With human bladder cancer
cells, a decreased DNA synthesis and induced apoptosis
was observed in a dose-dependent manner (Oh et al., 2003).
In skin cancer in mice, CLA at 1.5% (wt/wt) reduced
papilloma incidence from wk 8 to 24, whereas after 24 wk
of tumor promotion tumor yield was inhibited at 1.0 or
1.5% (Belury et al., 1996), suggesting that inhibition of
tumor promotion by CLA is independent of its antiinitiator
activity.
In a few studies related to human subjects, Aro et al.
(2000) observed a negative correlation of serum CLA and
TVA with breast cancer risk in postmenopausal women.
They found that the relative risk of breast cancer in these
women with higher CLA intake was 0.3 relative to lower
CLA intake, and when both CLA and TVA were combined,
relative risk was reduced to 0.2. The authors hypothesized
that a diet composed of CLA-rich dairy products may
protect against breast cancer in postmenopausal women,
even though it was not possible to assess the independent
effects of CLA in the study. In another epidemiological
study involving >25 years of follow-up in the Finnish breast
cancer research, Knekt and Jrvinen (1999) found an
inverse relation between intakes of milk and dairy products
with incidence of breast cancer and suggested that CLA

could be the factor involved. In French women (N=360),

number of tumors and incidence of tumor was less for CLA
enriched diets than for control diets (Lavillonniere and
Bougnoux, 1999). A proposition has been made that CLA
specifically up-regulates cell signal systems at the level of
gene expression (mRNA and protein) that are responsible
for the induction of apoptosis in human breast and prostate
cancer cells (Wahle and Heys, 2002). Although such
findings are quite compelling, they cannot be taken as
definitive. Further epidemiological, clinical, and
intervention studies are needed to come to a definite
conclusion before CLA can be used as an anticancer drug. It
is more imperative because one Netherlands cohort study on
diet and cancer in relation to postmenopausal breast cancer
could not confirm the relationship of CLA with inhibition of
cancer as has been observed in animal and tissue culture
models (Voorips et al., 2002). Similarly no association
between the level of CLA in the breast adipose tissue at the
time of breast cancer diagnosis and the subsequent
development of metastasis was observed in a cohort of 209
patients with an initially localized breast cancer (Chajes et
al., 2003).
The effects of specific isomer(s) of CLA responsible for
anticancer properties are not conclusive. Initially it was
thought that c-9, t-11 CLA was responsible for the
anticancer properties. However, t-10, c-12 has been found
to be equally or even more potent than its c-9, t-11
counterpart (Ochoa et al., 2002; Ip et al., 2003), probably
due to its antiadipogenic effects (Pariza et al., 2001;
Terpstra et al., 2002) and cancer being related to obesity.
Another study, however, showed that a mixture of c-9, t-11
and t-10, c-12 isomers was more potent than either of the
two individual isomers (Majumdar et al., 2002). In yet
another study, growth factor-induced proliferation of breast
cancer cells were inhibited by both c-9, t-11 and t-10, c-12
isomers, with c-9, t-11 isomer exhibiting the strongest effect
(Chujo et al., 2003). Recently, however, Tanmahasamut et
al. (2004) showed c-9, c-11 to be more potent than either of
the c-9, t-11 or t-10, c-12 isomers against human breast
cancer cells. In human prostate cancer cell line, the
antiproliferative effects of c-9, t-11 and t-10, c-12 CLA as
well as their mixture were not equivalent and different
pathways were involved for individual isomers (Ochoa et
al., 2004). While t-10, c-12 isomer appeared to work
preferentially through modulation of apoptosis and cell
cycle control, c-9, t-11 worked through arachidonic acid
metabolism (Ochoa et al., 2004). It is possible that the
biopotency of individual isomers or their mixture depends
on the cell type, organ, stage of tumerogenesis, and the
species of animal used in the study.
It has been mentioned above that the mechanisms of
action of CLA are not very clear, which may differ between
the two major isomers concerned. It is also equally

POTENTIAL HEALTH BENEFITS OF CLA

reasonable to find different mechanisms in different cell
types, stage of tumerogenesis, and species of animals.
Potential mechanisms of action of CLA have been described
in detail in recent reviews (Banni et al., 1999; Kritchevsky,
2000; Pariza et al., 2000; Banni et al., 2003; Pariza et al.,
2003). Mechanism of action of CLA proposed thus far has
been summarized below, but how the link between many of
these potential mechanisms could be established to clearly
define its role in various forms and stages of cancer remains
to be further researched.
Triggers apoptosis through up-regulation of cell signal
systems at the level of gene expression, both mRNA and
protein (Wahle and Heys, 2002) or through oxidative stress
mediated by protein kinase c and NADPH oxidase pathway
(Bergamo et al., 2004),
Decreases endothelial cell proliferation induced by basic
fibroblast growth factor (Moon et al., 2003), and serum and
mammary gland VEGF (Ip et al., 2003), all of which are
potent angiogenic factors expressed in many tumors
including mammary gland,
Activates peroxisome proliferator-activated receptors
(PPAR; Moya-Camarena et al., 1999; Belury, 2002a),
Activates transcription factors regulating gene
expression with respect to cell growth, differentiation, and
apoptosis (Majumdar et al., 2002),
Downregulates cyclooxygenase-2 activity related to
carcinogenesis and inflammation (Watkins et al., 1999;
Iwakiri et al., 2002),
Modulates arachidonic acid metabolism and reduces
PGE2 and cytokines (Banni et al., 1999; Urquhart et al.,
2002; Iwakiri et al., 2002; Ochoa et al., 2004),
Decreases DNA synthesis associated with angiogenesis
(Oh et al., 2003; Moon et al., 2003) and modulates DNA
adduct formation (Majumdar et al., 2002),
Reduces nitric oxide and nitric oxide synthase (Iwakiri
et al., 2002),
Increases retinal, which influences gene expression
through activation of PPAR (Carta et al., 2002),
Reduces free radical induced oxidation (Belury,
2002a,b; Yu et al., 2002),
Blocks cell cycle in the mitotic division of cancer cells
(Liu et al., 2002; Ochoa et al., 2004),
Downregulates expression of estrogen receptors bpth at
mRNA and protein levels and decreases the binding activity
of nuclear protein to estrogen (Tanmahasmut et al., 2004),
Inhibits IGF-I receptor signaling pathway implicated in
the development of bladder cancer (Oh et al., 2003) or
reduces IGF-II secretion (Cho et al., 2003b),
Downregulates ErbB2 and ErbB3 mRNA and protein
levels (Cho et al., 2003a).
The lowest dose shown to be effective against
mammary cancer in rats was 0.1% of the diet (Ip et al.,
1999). Both free-fatty acid and triglyceride-CLA were

1319

essentially identical in their anticancer properties (Ip et al.,

1995). This may have practical implications in human
health, because the CLA present in foods from ruminants is
mostly in triglyceride form and a mere intake of such CLAenriched foods may help us derive the health benefits of
CLA. At the 0.5% dose level, the anticancer activity of c-9,
t-11 and t-10, c-12 CLA was very similar, even though
accumulation of t-10, c-12 CLA in the mammary tissue was
considerably less than that of c-9, t-11 CLA (Ip et al., 2002).
The anticarcinogenic effects of both the isomers were
greater at higher concentrations, >0.25% than at 0.1% of
diet, with a proposition that the effects of the two isomers
might not be additive (Hubbard et al., 2003). No adverse
effect of a mixture of c-9, t-11 and t-10, c-12 CLA isomers
in rats at 2,433 mg/kg bw for males and 2,728 mg/kg BW
for females have been observed (OHagan and Menzel,
2003). It may have practical implications in human health in
developing the drugs once the mechanism of action and the
effective dose of CLA have been determined.
It was pointed out above about a possible hypothesis of
TVA being converted to CLA in non-ruminants. It was
based on the observations of higher concentrations of CLA
in the mammary gland and other tissues for rats fed CLAenriched butterfat than rats fed synthetic CLA isomers at the
same dietary level (Ip et al., 1999). In rats fed TVA and c-9,
t-11 CLA, conversion of dietary TVA to c-9, t-11 CLA
resulted in a dose-dependent increase in the accumulation of
c-9, t-11 CLA in the mammary fat pad, which was
accompanied by a parallel decrease in tumor formation in
the mammary gland (Corl et al., 2003). Similarly, after 4 d
of incubation of SW480 and MCF-7 cancer cells with TVA
at 5 and 20 microg/mL, c-9, t-11 CLA increased from
undetectable levels to 8.57 and 12.14 g/100 g fatty acid
methyl esters in cellular lipids, respectively (Miller et al.,
2003a). These findings not only confirmed the conversion
of TVA to c-9, t-11 CLA in non-ruminants, but also showed
TVA to be equally important for cancer prevention as the
dietary supply of c-9, t-11 CLA. Furthermore, it will also
enhance the nutritional and therapeutic value of milk and
meat from ruminants in preventing various forms of cancer.
CLA and diabetes
The role of CLA in regulating type-2 diabetes, which is
linked to obesity, is not only complex and not so well
understood, but also conflicting at times. Since t-10, c-12
CLA is linked to decreased body fat, it is this isomer that is
implicated as an antidiabetic. It has been shown that CLA
was as equally effective as thiazolidinediones, a class of
oral insulin sensitizing agents that improve glucose
utilization without stimulating insulin release, in reducing
fasting glucose in Zucker diabetic rats (Belury and Vanden
Huevel, 1999). In a double blind study with human
diabetics, Belury (2002b) showed a decreased blood

1320

R. C. KHANAL

Table 3. Biological effects of CLA on atherogenesis, adipogenesis, bone metabolism, and immune functions
Study/model/cell line
Effects
A. On adipogenesis
Mice and rats5
Increased UCP2 expression in rats/no effect in mice
Reduced body weight and leptin
Type II diabetic subjects6
Increased fat oxidation and O2 consumption
Male stD ddY mice7
Healthy, weight-stable women8
No effect on FA and glycerol metabolism
Transient decrease in leptin, no effect on plasma glucose or lactate
Healthy women9
Reduced brown and white adipose tissue,
ICR and C57BL/6J mice10
Increased expenditure and loss of energy
Balb-C mice11
Weaned piglets fed high-fat diet12
No effect on adipocity
Reduced body fat mass
Overweight and obese humans13
No change in body composition, or weight
Abdominally obese men14
No effect on body composition and energy expenditure
Women (20-41 yr age)15
B. On atherogenesis
Reduced severity of lesions
Rabbits1
Reduced atherosclerosis in aortas
Rabbits2
Rabbits3
Inhibited atherogenesis, established atherosclerosis regressed
Reduced aortic fatty streak and total cholesterol
Hamsters4
C. On immunity
Enhanced immune response with protection against collateral damage
Several16
Nursery pigs17
Enhanced lymphocyte proliferation
No change in immune status
Young healthy women18
D. On bone metabolism
Reduced eicosanoid production
Rats19
Rats20
Increased collagen synthesis
E. On oxidation
Protection from H2O2 or cumene H2O2
In vitro21
Quenched free radicals
Cell culture22
In vitro23
Increased total oxyradical scavenging capacity
Microsomes/mitochondria protected from H2O2
Rat liver24

Isomer*
d
b
c
c
c
d
c
c
a/b
b
c
a/b
d
c
c
c
c
c
c
c
a/b
a
b
d

* a=c-9, t-11, b=t-10, c-12, a/b=c-9, t-11 and t-10, c-12, c=mixture, d=not known.
1
Kritchevsky (2003), 2 Lee et al. (1994), 3 Kritchevsky et al. (2000), 4 Nicolisi et al. (1997), 5 Ealey et al. (2002), 6 Belury et al. (2002), 7 Ohnuki et al. (2001),
8
Zambell et al. (2001), 9 Medina et al. (2000), 10 Takahashi et al. (2002), 11 Terpstra et al. (2002), 12 Demaree et al. (2002), 13 Blankson et al. (2000), 14 Risrus
et al. (2002), 15 Zambell et al. (2000), 16 Cook et al. (2003), 17 Bassaganya-Riera et al. (2001), 18 Kelley et al. (2000), 19 Li and Watkins (1998), 20 Watkins et
al. (1999), 21 Su et al. (2003), 22 Yu et al. (2002), 23 Leung and Liu (2000), 24 Palacios et al. (2003).

glucose and plasma leptin in CLA supplemented patients.

Belury et al. (2003) suggested that t-10, c-12 isomer may be
the bioactive isomer of CLA that influences the body
weight changes observed in subjects with type-2 diabetes.
Although serum insulin was higher in CLA fed rats than
thiazolidinediones treated rats, it was only half the amount
observed in control rats (Belury and Vanden Huevel, 1999).
Later, Henrickson et al. (2003) demonstrated that the
improved glucose tolerance and insulin-stimulated glucose
transport in the skeletal muscle of obese Zucker diabetic
rats was due to t-10, c-12 isomer with no effect due to c-9,
t-11 isomer. In contrast, t-10, c-12 isomer of CLA was
shown to induce hyperinsulinemia and fatty liver in mice
with no effect due to c-9, t-11 isomer (Clment et al., 2002).
Similarly, t-10, c-12 isomer of CLA promoted insulin
resistance, increased serum glucose and insulin
concentrations, whereas c-9, t-11 isomer had ameliorative
effect on lipid metabolism in ob/ob mice (Roche et al.,
2002). Similarly, Brown et al. (2003) demonstrated that t-10,
c-12 isomer of CLA decreased insulin-stimulated glucose

uptake and metabolism in differentiating human

preadipocytes. Some of the pertinent findings about the role
of CLA in diabetes are presented in Table 2.
The initial proposition about the activation of PPAR in
modulating diabetes (Belury and Vanden Heuvel, 1999;
Moya-Camarena et al., 1999) seems to be questioned with a
new finding that showed a decreased expression of PPAR
by t-10, c-12 (but not c-9, t-11) in adipocytes, which could
promote insulin resistance and oppose the hypoglycemic
actions of thiazolidinediones in vivo (Brown and McIntosh,
2003; Brown et al., 2003). This could be the reason why
Risrus et al. (2002) found an increased insulin resistance
and glycemia in abdominally obese men when treated with
3.4 g/d of t-10, c-12 isomer of CLA. Some of the concerns
about insulin resistance in humans (Risrus et al., 2002) and
mice (Roche et al., 2002) as well as fatty liver associated
with CLA (Clment et al., 2002) could probably be
eliminated with arginine-CLA (Kim et al., 2004), because
arginine infusion is known to have a preventive role in the
insulin resistance by decreasing total plasma homocysteine

POTENTIAL HEALTH BENEFITS OF CLA

concentration (Cassone Faldetta et al., 2002). Put together,
the effects of CLA on type-2 diabetes are not very clear and
therefore further research on the effects, doses, and
mechanisms of action of CLA is warranted.
CLA and lipid metabolism
Many of the effects of CLA mentioned above appear to
stem from its ability to modulate lipid metabolism in
animals, humans, and cell culture studies (Table 3). A major
effect of CLA in this respect is the reduction of lipid uptake
by adipocytes (Pariza et al., 2003), which leads to the
reduction in body fat gain (Kim et al., 2002b). Both isomers
of CLA were effective in reducing body fat in mice, with c9, t-11 being more effective in females than in males
(Chardigny et al., 2003). Feeding mice a diet with 0.5% t10, c-12 CLA for 4 weeks reduced body fat gain, serum
leptin levels, and adipocyte leptin mRNA expression
without affecting feed intake or body weight (Kang and
Pariza, 2001). Granlund et al. (2003) demonstrated that t-10,
c-12 CLA prevented lipid accumulation in humans and
mouse adipocytes at very low concentrations. Dietary CLA
altered adipose tissue and milk lipids of pregnant and
lactating sows and influenced the growth and tissue
composition of weaned pigs (Bee, 2000a,b). Similarly, CLA
decreased backfat, shoulder fat as well as carcass fat in pigs,
with results more pronounced in females than in males
(Dunshea et al., 2002). There was, however, no effect of
CLA on adiposity of early-weaned piglets fed high fat diets
(Demaree et al., 2002). In chicks, supplementation of CLA
in the diet linearly increased its proportion in leg muscle
(An et al., 2003), making it a potential source of CLA for
humans. However, excessive dietary CLA also resulted in
increased liver weight, hepatic lipid accumulation, and
serum glutamic-oxaloacetic transaminase (An et al., 2003).
Serum glutamic-oxaloacetic transaminase is particularly
important, because it is the most sensitive indicator of tissue
damage in avian species (Lumeij, 1997). In dairy cows, t-10,
c-12 CLA reduces milk fat content, lipogenic rates, and
expression of genes involved in milk lipid synthesis
(Baumgard et al., 2001; 2002) and coordinates suppression
of mRNA abundance for mammary enzymes involved in
milk fat synthesis (Peterson et al., 2003).
Azain et al. (2000) reported that the reduction in body
fat mass in rats was the result of reduced adipose tissue cell
size rather than cell number. Similarly, Poulos et al. (2001)
found a reduction in cell size, but not the cell number, in
rats that had less body fat in response to CLA
supplementation. Such a decrease in body fat of mice fed
CLA could also be due to an increase in energy expenditure
(West et al., 2000; Terpstra et al., 2002) and energy loss in
the excreta (Terpstra et al., 2002). Even a single dose of a
mixture of CLA administered orally appeared to enhance
energy metabolism in mice through increased fatty acid

1321

oxidation and sympathetic nervous activity (Ohnuki et al.,

2001). Moreover, CLA affected the gene expression of
proteins regulating energy metabolism in mice (Takahashi
et al., 2002). Another way CLA reduces fat mass in mice is
through apoptosis and lipodystrophy via tumor necrosis
factor and uncoupling protein 2 (Tsuboyama-Kasaoka et
al., 2000). Apoptosis of mice adipose tissues occurred
within 5 days of consuming a diet containing CLA (Miner
et al., 2001). Evans et al. (2000) found the effects of t-10, c12 isomer to be more pronounced than those of the crude
mixture of CLA isomers. They further suggested that CLAs
antiobesity effects were through inhibition of proliferation,
increased FA oxidation, attenuating triglyceride content,
and/or inducing apoptosis in preadipocytes. In another study,
prevention of lipid accumulation in human and mouse
preadipocytes by t-10, c-12 CLA was achieved through
modulation of PPAR (Granlund et al., 2003).
Downregulation of 9-desaturase gene expression in
adipocytes by t-10, c-12 isomer of CLA may contribute to
the mechanisms by which CLA reduces body fat in mice
(Choi et al., 2000). Such a loss of 9-desaturase function
protects mice against adiposity and one of the consequences
of 9-desaturase deficiency is an activation of lipid
oxidation in addition to reduced triglyceride synthesis and
storage (Ntambi et al., 2002). This is important because
over expression of 9-desaturase is related to genetic
predisposition to hepatocarcinogenesis in mice and rats
(Falvella et al., 2002).
Determination of whether the body composition effects
observed in animal models are applicable to humans is very
important. Banni et al. (1999) suggested that the
anticarcinogenic action of CLA stems from its metabolism
and influence on tissue lipid metabolism, which CLA
appears to modulate in a myriad of ways. In human subjects
with type-2 diabetes, Belury et al. (2003) suggested that t10, c-12 is the bioactive isomer that influences the body
weight changes. In overweight and obese humans, CLA
reduced body fat mass (Blankson et al., 2000). Smedman
and Vessby (2001) showed a reduction in body fat in
humans without affecting body weight when healthy men
and women were supplemented with 4.2 g/d of a mixture of
CLA containing equal amounts of t-10, c-12 and c-9, t-11
isomers. Noone et al. (2002) showed a significant
improvement in fasting triglyceride and very low density
lipoprotein metabolism in healthy human subjects when 3
g/d of a blend of c-9, t-11 and t-10, c-12 (50:50 or 80:20)
CLA was supplemented in the diet. Lipogenesis was
inhibited by t-10, c-12 but not c-9, t-11 isomer in primary
cultures of stromal vascular cells from human adipose
tissue (Brown et al., 2001). In contrast, a mixture of CLA
had no significant effect on body composition, energy
expenditure, fat oxidation, and respiratory exchange ratio at
rest or during exercise in healthy adult women (Zambell et

1322

R. C. KHANAL

al., 2000). Such differences on human adiposity may be the

result of different mixtures and levels of CLA isomers and
diverse subject populations (Evans et al., 2002).
To sum up, potential antiobesity mechanisms of CLA
include decreased preadipocyte proliferation and
differentiation into mature adipocytes, blocking of cell
cycle during mitotic division, apoptosis of the adipocyte
cells, decreased fatty acid and triglyceride synthesis,
downregulation of key lipogenic enzymes, and increased
energy expenditure, lipolysis, and fatty acid oxidation.
Carta et al. (2002) went one step further and concluded that
a regular intake of CLA and/or TVA as its precursor should
work as an excellent preventive agent that would modulate
lipid metabolism in target tissues thus conferring protection
against different health problems associated with obesity.
However, Loor et al. (2003) suggested that consumption of
CLA supplements containing t-10, c-12 be avoided during
nursing period because of its negative effects in body
weights and carcass fat, protein, and ash contents.
CLA and atherosclerosis
Lee et al. (1994) showed initially that CLA has an
antiatherosclerotic effect in rabbit aortas. There was a 34%
reduction in atherosclerosis in rabbits when CLA was
included at 0.1% of the diet for 12 weeks, which increased
to 64% when included at 0.5% of the diet with a slight
reduction to 58% at 1% of the diet (Lee et al., 1994). A
significant reduction in total cholesterol, non-high density
lipoprotein cholesterol, and aortic fatty streak areas in
hamsters occurred even at 0.06% of CLA in the diet
(Nicolisi et al., 1997). Inhibition of atherosclerosis and
regression of established atherosclerosis (Kritchevsky et al.,
2000) as well as a reduction in the severity of established
lesions (Kritchevsky, 2003) in rabbits has been observed.
Sher et al. (2003) showed a reduction in plasma cholesterol
during cholesterol supplementation, but accentuation of the
atherogenic lipid profile during acute phase response in
hamsters when CLA was supplemented in the diet at 1%.
Since a mixture of CLA isomers was used in most of these
studies, the effects of specific isomers is not known. Some
of the important findings about the effects of CLA on
atherosclerosis are presented in Table 3.
Since it is difficult to study the effect of CLA on
atherosclerosis in humans, an indirect approach by
measuring various potential heart disease markers is
required (Belury, 2002a). Lipid atherogenic risk markers
were more favorably influenced by c-9, t-11 isomer than a
mixture of CLA or fish oil (Valeille et al., 2004). When
healthy human subjects were used in a double-blind placebo
controlled intervention trial, Noone et al. (2002)
demonstrated that a blend of c-9, t-11 and t-10, c-12
isomers (80:20 and 50:50) improved very low-density
lipoprotein cholesterol and plasma triacylglycerol

metabolism suggesting that some of the cardio-protective

effects of CLA shown in animal studies were relevant to
humans as well. However, there was no effect of
supplementing CLA on total cholesterol or high-density
lipoprotein cholesterol in healthy human subjects (Mougios
et al., 2001). In another study in humans, supplementation
of CLA did not affect any of the atherogenic parameters
(Benito et al., 2001). In totality, these results indicate that
antiatherogenic properties of CLA are not definitive.
CLA and immune system
Enhanced immune function is usually associated with
anorexia and wasting. In a detailed review, Cook et al.
(2003) showed that CLA not only enhances immune
response, but also protects tissues from collateral damage
(Table 3). Sugano et al. (1999) proposed that the immune
enhancing effect of CLA was by modulating eicosanoid and
immunoglobulin production. Whigham et al. (2000)
concluded that t-10, c-12 isomer competitively inhibited the
conversion of arachidonic acid to prostaglandin E2. CLA
also diminished lipopolysaccharide-induced inflammatory
events in macrophages through reduced mRNA and protein
expression of nitric oxide synthase and cyclooxigenase-2 as
well as subsequent production of nitric oxide and
prostaglandin E2 (Cheng et al., 2004), both of which are
also implicated in carcinogenesis. Cook et al. (1999)
suggested that CLA prevents immune associated wasting by
protecting nonlymphoid tissues from the adverse effects of
cytokines, which are growth suppressants, because CLA
influences the immune system by altering the effects of
cytokine,
interleukin,
leukotriene
and
many
immunoglobulins (Sbdio et al., 2000). Although dietary
CLA enhanced antibody production in broiler chickens
(Takahashi et al., 2003), ameliorated viral infectivity in a
pig model of virally induced immunosuppression
(Bassaganaya-Riera et al., 2003), and enhanced lymphocyte
proliferation in nursery pigs (Bassaganaya-Riera et al.,
2001), no change in immune status was observed in young
healthy women (Kelley et al., 2000). Whigham et al. (2002)
indicated that CLA might induce a change in immune
response in favor of cell-mediated response rather than an
allergic one, while Nichenametla et al. (2004) showed a
higher natural killer cell cytotoxicity in rats fed CLA in diet
than the control group without CLA. It appears that c-9, t11 and t-10, c-12 isomers of CLA stimulate different
immunological events in mice with c-9, t-11 increasing
tumor necrosis factor while t-10, c-12 increasing
immunoglobulin A and M production (Yamasaki et al.,
2003). In a double blind parallel reference-controlled
intervention study in adult humans, almost twice as many
subjects reached protective antibody levels to hepatitis B
when consuming a 50:50 mixture of c-9, t-11 and t-10, c-12
CLA isomers for 12 weeks compared with sunflower oil fed

POTENTIAL HEALTH BENEFITS OF CLA

reference subjects, but the response to 80:20 mixture of c-9,
t-11 and t-10, c-12 CLA was similar to that of reference
(Albers et al., 2003). This is probably the first of its kind
about the effects of CLA on immune function using actual
human subjects and may open new vistas for CLA research.
The implications of immunomodulatory effects of CLA on
livestock production would probably be in enhancing the
response of animals to vaccination and conferring disease
resistance. To date there have been limited attempts at
identifying the effects of specific isomers of CLA on the
immune system.
CLA and bone metabolism
Watkins et al. (1996) found a higher rate of bone
formation in chicks fed butterfat, which was suggested to be
due probably to increased CLA intake. Dietary CLA led to
differences in CLA enrichment of various organs and
tissues, bone marrow and periosteum containing the highest
concentrations of CLA and brain the lowest (Li and Watkins,
1998). Enrichment of chondrocytes with CLA affected
collagen synthesis in a dose dependent fashion (Watkins et
al., 1999). Reduced production of arachidonic acid and
PGE2 in the chondrocytes was suggested to be the possible
mechanism (Watkins and Siefert, 2000). Such changes in
bone biomarkers and bone formation rates in rats were
associated with increased c-9, t-11 CLA in bone tissue
lipids (Watkins et al., 2003). Furthermore, dietary beef fat
and a CLA supplement were able to maintain synthetic
activity of osteoblastic cells and CLA was even able to
rescue the reduced bone formation rate in rats given a diet
high in -6 FA (Watkins et al., 2003). McDonald (2000)
suggested increased ash content in CLA fed animals (Park
et al., 1999) is due to protection of bone loss from cytokines.
Further investigation is needed as to how bone metabolism
is affected by CLA and mechanism of action related with it.

1323

reported a stronger oxyradical scavenging capacity for t-10,

c-12 than c-9, t-11 isomer. In rat liver, CLA was more
effective than vitamin A in protecting microsomes or
mitochondria from peroxidative damage (Palacios et al.,
2003). These results indicate that both t-10, c-12 and c-9, t11 isomers of CLA are effective antioxidants. Kim et al.
(2004) investigated the antioxidant activities of arginineCLA, a water-soluble salt. They found free radical
scavenging capacity of arginine-CLA was double that of
CLA with its antioxidant activity similar to vitamin E.
Arginine-CLA may have further implications in expanding
the scope of the application of CLA as a health-promoting
agent because of its solubility in water.
IMPLICATIONS
Diverse biological roles of CLA in mediating cancer,
diabetes, lipid metabolism, atherosclerosis, immune
function, bone modeling etc. observed in animal models are
quite compelling. Although there have been a few attempts
at verifying the positive effects of CLA in human health
through case control studies, it is not yet possible to clearly
state that CLA supports all those benefits in humans as well.
Limited available literature in humans, however, also
supports the findings observed in animals and tissue culture
models even though the results are inconclusive and even
conflicting at times. Mechanisms of action with respect to
each isomer or a mixture of CLA isomers vis--vis its
physiological roles remains speculative, which demands
further research and thoughtful insight to put together the
bits and pieces associated with the changes brought about
by CLA. Dose related studies, both in animals and in
humans, are very limited. In spite of so much research
efforts, testing CLA in clinical trials is still remote. Further
experimentation is warranted in characterizing the doseresponse profile of each or a mixture of CLA isomers with
each of the physiological role associated with it, both under
in vivo and in vitro conditions. As a result, natural
enrichment of food products through manipulation of
animal diet may contribute to the overall goal of obtaining
the positive health benefits associated with CLA in the
immediate future.

CLA and oxidation

Some of the potential health benefits of CLA appear to
be mediated through its antioxidant properties (Table 3). Yu
et al. (2002) showed that both c-9, t-11 and t-10, c-12
isomers of CLA quench free radicals. It was also shown that
the mixture of both isomers was more effective than either
isomer alone. When the effect of CLA on paraoxygenase 1,
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