Critical Reviews in Food Science and Nutrition, 46:479488 (2006)

Copyright
C Taylor and Francis Group, LLC

ISSN: 1040-8398
DOI: 10.1080/10408390600723953

Conjugated Linoleic Acid Intake

In Humans: A Systematic Review
Focusing on Its Effect on Body
Composition, Glucose, and Lipid
Metabolism

J. SALAS-SALVADO, F. MARQUEZ-SANDOVAL, and M. BULLO

Unitat de Nutricio Humana, Hospital Universitari de Sant Joan de Reus, Departament de Bioqumica i Biotecnologia,
Facultat de Medicina i Ciencies de la Salut de Reus, Universitat Rovira i Virgili.

Studies performed on different species show that the consumption of conjugated linoleic acid (CLA) leads to a loss of
fat and total body weight, reduces the plasma concentrations of total and LDL cholesterol, and has an antiinflammatory
effect. This article reviews the clinical trials on human beings that evaluate how mixtures of CLA isomers administered
as supplements or CLA-enriched products can affect total body weight, body composition, plasma lipid profile, glycemia,
insulinemia, insulin sensitivity, lipid oxidation, and inflammation. After analyzing the few studies published to date in reduced
samples of healthy humans or patients with overweight, obesity, metabolic syndrome, or diabetes, we deduce that there is not
enough evidence to show that conjugated linoleic acid has an effect on weight and body composition in humans. However,
some of these studies have observed that the administration of various CLA isomers has adverse effects on lipid profile (it
decreases HDL cholesterol concentration and increases Lp(a) circulating levels), glucose metabolism (glycemia, insulinemia
or insulin sensitivity), lipid oxidation, inflammation, or endothelial function. Therefore, long-term randomized clinical trials,
controlled with placebo, need to be made in large samples of patients to evaluate the efficacy and safety of CLA isomers
before its indiscriminate use in human beings can be recommended.

Keywords conjugated linoleic acid, body composition, weight, glucose metabolism, lipid metabolism

INTRODUCTION Obesity is a condition with a multifactorial aetiology, involv-

Obesity is a chronic metabolic and nutritional disorder that
has serious consequences on health. Although clinical and
epidemiological knowledge about this disease has improved,
the prevalence of obesity has increased enormously in recent
decades in both industrialized and developing countries (Wang
and Jones, 2004a). For this reason, and specially because obesity
is a risk factor for the onset of diabetes, cardiovascular diseases,
some cancers, and other conditions, obesity can be considered
an important public health problem at present (Wang and Jones,
2004a; Belury, 2002).
Address Correspondence to Jordi Salas-Salvado, Unitat de Nutricio
Humana, Departament de Bioqumica i Biotecnologia, Facultat de
Medicina i Ciencies de la Salut. C/Sant Llorenc, 21 43201 Reus, Spain.
E-mail: jss@fmcs.urv.es
ing genetic and environmental factors. Among them, it has been
suggested that diet, or some aspects of diet, and the lack of
physical activity may explain why the prevalence of obesity has
increased over time. It has been suggested that one of the dietary
factors that has an important effect on controlling energy bal-
ance regulation is the content of conjugated linoleic acid (Brown
and McIntosh, 2003; Fernandez-Quintela et al., 2004; Pariza,
2004).
Conjugated linoleic acid (CLA) is the name given to a group
of unsaturated fatty acids with 18 carbon atoms, and a mixture of
positional and geometrical isomers with two conjugated double
bonds (unlike linoleic acid, which has a non-conjugated diene).
The two double bonds in CLA are usually in the C-9 and C-11
or C-10 and C-12 positions, and can be in either the cis or trans
configurations (Basu et al., 2000). These isomers are minority
components in the lipid fraction, and they are mainly found in

479
480 J. SALAS-SALVADO ET AL.
the meat from cows and sheep, and the corresponding dairy
products (Thomas et al., 2003; Larsen et al., 2003).
CLA isomers have been extensively studied (specially
trans10cis12 and cis9trans11 in different concentrations) be-
cause of their ability to modulate cancer, prevent arteriosclero-
sis, modulate diabetes, improve the immunological function, and
modify body composition in animals (Wang and Jones, 2004b;
Gaullier et al., 2005). Unfortunately, fewer studies have been
carried out in humans, and very few have proved to be effective
at controlling these conditions in our species (Whigham et al.,
2000).
Several studies have suggested that CLA could have ben-
eficial effects on body composition, and lipid or glucose
metabolism (Riserus et al., 2004). However, the studies made
to date on humans are highly contradictory in this respect:
(Terpstra, 2004) some observe that the consumption of CLA iso-
mers has beneficial effects (Gaullier et al., 2004; Blankson et al.,
2000) while others observe harmful effects (Pariza, 2004). In
fact, two recent reviews have concluded that CLA supplements
are not very effective as weight loss agents for humans although
no systematic analysis is made of how these supplements affect
glucose, lipid metabolism, and other arteriosclerotic risk factors
(Larsen et al., 2003; Terpstra, 2004).
The fact that the consumption of CLA may affect energy
balance and body composition has meant that various sectors of
the food industry have considered incorporating CLA in higher
doses than the ones that exist naturally in some foods. Some of
these products, which are claimed to have beneficial effects on
the loss of fat, are on the market and can be easily acquired by
any consumer (dairy products, lyophilized natural foods, etc.).
Also on sale at present, and easily obtainable, are CLA in the
form of dietary supplements.
The aim of the present study is to make an extensive system-
atic bibliographical review of the human intervention studies
published to date analysing how CLA can affect body composi-
tion and other cardiovascular risk factors.
EFFECT OF CLA ON THE REGULATION OF
ADIPOSITY AND INSULIN SENSITIVITY:
MECHANISMS INVOLVED
Several studies in animals and humans have related CLA to
energy metabolism or weight regulation, and an improvement
in the lipid and glucose profile (Choi et al., 2004; Taylor et al.,
2004; Wang and Jones, 2004b). More recently, the decrease in
the production of proinflammatory cytokines and the overpro-
duction of cytokines with anti-inflammatory capacity have also
been related to the administration of conjugated linoleic acid
(OSeha et al., 2004; Song et al., 2005). The biochemical and
molecular mechanisms that underlie the effects of CLA in the
organism have been extensively studied in some experimental
models and also in several cell types. In fact, several studies sup-
port the hypothesis that many of the effects of conjugated linoleic
acid may be explained by the activation of the PPAR receptors
and the stimulation of the production of some proinflammatory
cytokines, particularly the TNF- (Tsuboyama-Kasaoka et al.,
2000).
CLA Mechanisms for Controlling Body Weight
Body weight has been observed to decrease after the admin-
istration of CLA, particularly in its isomeric form trans10cis12,
in several animal models (AKR/J, Balb-C and C57BL/6J mice,
Sprague-Dawley and Zucker rats, etc) (Wang and Jones, 2004b).
Although some studies have shown a decrease in energy intake
in animals treated with CLA (Thomas et al., 2003; Mensink,
2005; Terpstra et al., 2003), others have found that there is no
effect or that the reduction in fat deposition is not related to the
magnitude of the decrease in the energy intake. Therefore, other
mechanisms such as reducing the adipocyte size, modifying
adipocyte differentiation, stimulating apoptotic mechanisms or
regulating lipid metabolism have also been implicated (Larsen,
2003; Mirand et al., 2004; Kloss et al., 2005; Chardingny et al.,
2003).
In relation to this, several studies have described the stim-
ulatory effect of CLA administration on UCP protein expres-
sion in brown and white adipose tissue, and also in the liver
of rats and mice, thus contributing to a higher metabolic rate
(Takahashi et al., 2002; Roche et al., 2002; Kang et al., 2004;
Choi et al., 2004; Javadi et al., 2004; Warren et al., 2003;
Metges et al., 2003). Likewise, in both preadipocyte cells and
animals, a notable decrease in adipocyte size has been observed,
favoring the proliferation of small adipocyte cells to the detri-
ment of the proliferation of hyperplastic adipocytes after stim-
ulation with CLA (Tsuboyama-Kasaoka et al., 2000; Evans
et al., 2002). Mechanisms of cell differentiation regulated by
transcription factors such as C/EBP and PPAR also seem to
be significantly inhibited by the various CLA isomers (Brown
and McIntosh, 2003; Kang et al., 2003) with the correspond-
ing failure in the differentiation of preadipocytes in mature and
functional adipocytes. This lower capacity for cell differentia-
tion, together with the increase in the apoptotic processes stimu-
lated by CLA and the fact that these fatty acids stimulate TNF
synthesis (Tsuboyama-Kasaoka et al., 2003) would explain why
the overall net effect is a decrease in the size of fat depots.
Effects of CLA on Insulin Resistance
Just as has been suggested in humans, various studies car-
ried out in experimental animal models have shown that CLA
can have adverse effects on insulin metabolism (Ohashi et al.,
2004; Taylor et al., 2004; Sun et al., 2003; Kelley and Erick-
son, 2003). The regulation of some cytokines and similar sub-
stances mediated by CLA may explain at least some of these
effects.
 CONJUGATED LINOLEIC ACID INTATE IN HUMANS
The importance of leptin in glucose and insulin metabolism
has been widely characterized (Kamohara et al., 1997; Cusin
et al., 1998; Nagao et al., 2003). It has been suggested that the
dose-dependent reduction of circulating leptin levels observed
after CLA supplementation explains the associated insulin re-
sistance (Ohashi et al., 2004; Hargrave et al., 2003; Larsen et al.,
2003; Belury et al., 2003). Although CLA has been considered
as an anti-inflammatory compound, recently the effect of CLA
on the activation of the nuclear factor kB (NFkB) in primary
cultures of human adipocytes has been described (Chung et al.,
2005; De Roos et al., 2005; Poirier et al., 2005). This transcrip-
tional factor regulates the expression of several genes promoting
inflammation and cell survival such as TNF, IL-6 or IL-8. Be-
tween other roles, these cytokines decreases adipocyte GLUT4
expression, which hinders cell glucose consumption and, there-
fore, increases the circulating levels of insulin (Stephens and
Pekala, 1991; Winzell et al., 2006; Simon et al., 2006). TNF also
directly inhibits the activity of the insulin receptor through its
role in receptor phosphorylation (Hotamisligil, 1999; Choi et al.,
2004). Moreover, by modulating NFkB and ERK1/2, CLA de-
creases PPAR activity and the expression of adipogenic genes
that promote glucose and fatty acid uptake, such as ap2, GLUT4,
fatty acid synthase or lipoprotein lipase, and which leads to
insulin resistance and delipidation, at least in primary human
adipocytes (Chung et al., 2005).
Effects of CLA on the Lipid Metabolism
Studies carried out on experimental animal models consider
that CLA has a potential modulating effect on the formation
of the atheroma plaque. After daily administration of 0.5 g of
CLA in rabb its for 12 weeks, triglycerides and LDL choles-
terol levels decreased and the formation of the arteriosclerotic
plaque in the aorta was also observed to decrease (Corino et al.,
2002). Similar results have been observed in hamsters (Mitchell
et al., 2005; Valeille et al., 2005). These effects on the arte-
riosclerotic plaque are not observed after CLA consumption
in mice, although the reason for these differences is unknown
(Munday et al., 1999). Some studies suggest that the isomeric
form of the CLA administered (trans10,cis12 or cis9,trans11)
induces differences in fatty acid oxidation and the regulation
of certain enzymes (Macarulla et al., 2005). However, different
isomers do not seem to have a different effect on the progres-
sion and regression of the atheroma plaque (Kritchevsky et al.,
2004).
The modulatory effect of CLA on lipolytic and lipogenic en-
zyme expression and activity has also been widely reported. The
stimulation of lipolytic activity described in 3T3-L1 adipocyte
cells and human adipocytes, and therefore the increase in the
lipid oxidation rate could explain the decrease in the triglyceride
circulating levels secondary to the consumption of CLA (Evans
et al., 2002; Chung et al., 2005). Lypolitic activation, together
with the inhibited lipogenic activity described in preadipocyte
481
cell cultures may also explain why CLA can partly protect
against the development of obesity (Brown et al., 2001).
EFFECT OF CLA ON BODY COMPOSITION, LIPID
PROFILE, GLUCOSE METABOLISM, OXIDATION, AND
INFLAMMATION IN HUMANS
Materials and Methods
Data for this review were obtained by searching Medline or
PubMed and the ISI Web of Science with the key words:
CLA and humans, body composition and CLA, body
weight and CLA, and obesity and CLA, plasma lipids
and CLA, glucose metabolism and CLA, insulin sen-
sitivity and CLA, insulin and CLA, insulin resistance
and CLA, plasma cholesterol and CLA, plasma triglyc-
erides and CLA, CLA and inflammation, and CLA and
oxidation.
The criteria for selecting the studies were the following. They
had to be
a) randomized, double-blind clinical trials, controlled with
placebo,
b) carried out in humans,
c) published in a scientific journal in the database of the Science
Citation Index or Medline between 2000 and 2005,
d) original and
e) they must have evaluated changes in weight, body compo-
sition, plasma lipid profile, glycemia, insulinemia or insulin
sensitivity/resistance.
One study was not included in the review because it did not have
a placebo or a control group (Gaullier et al., 2005) and another
was not included because it was not an original paper (Belury
et al., 2003).
We finally selected 21 clinical trials to be included in
the review. Of these, 20 evaluated weight, 20 body composi-
tion, 19 plasma lipid profile, 14 parameters related to glucose
metabolism, and 5 lipid oxidation or inflammation. Once the
articles had been selected, the following significant data were
extracted:
author and year, number of participants (men/women), type
of individuals studied (normoweight, overweight or obese),
length of intervention, CLA dose administered (grams/day),
control of food intake and physical activity, composition of
the CLA administered, placebo used, changes in weight, lean
and fat mass observed, changes in the blood lipid profile,
changes in the glucose metabolism, and the methods used to
determine the body composition.
482 J. SALAS-SALVADO ET AL.
Results
Individuals Studied
Almost all of the 21 studies analysed were carried out in
small population samples that were heterogeneous as far as gen-
der, age, or body mass index were concerned. The study that
contained the highest number of individuals was by Gaullier
(2004), who investigated 180 overweight individuals. In total,
these 21 studies analyzed a sample of 910 individuals (430
women and 448 men). Some of the studies were performed
on normoweight subjects (Benito et al., 2001; Kreider et al.,
2002; Noone et al., 2002; Thom et al., 2001; Tricon et al., 2004;
Zambell et al., 2000), while others were performed on over-
weight (Riserus et al., 2004; Gaullier et al., 2004; Blankson
et al., 2000; Tricon et al., 2004; Berven et al., 2000; Kamphuis
et al., 2003; Malpuech-Brugere et al., 2004; Mougios et al., 2001;
Riserus et al., 2002a; Smedman and Vessy 2001; Petridou et al.,
2003; Desroches et al., 2005; Taylor et al., 2006) and obese sub-
jects (Riserus et al., 2004; Blankson et al., 2000; Tricon et al.,
2004 ; Berven et al., 2000 ; Riserus et al., 2001; Wihgham et al.,
2004; Taylor et al., 2006; Moloney et al., 2004), or patients with
metabolic syndrome (Riserus et al., 2001) or type 2 diabetes
(Moloney et al., 2004).
Design and Length of the Studies
Most of the studies analyzed were carried out without sub-
jecting the individuals to a strict control of nutrient or energy
intake (ad libitum). Very few of them were carried out on sub-
jects whose diet was strictly controlled (Benito et al., 2001;
Zambell et al., 2000; Kamphuis et al., 2003; Mougios et al., 2001;
Wihgham et al., 2004; Desroches et al., 2005). Studies on body
composition were carried out with the aim of analyzing body
weight or fat loss secondary to the CLA intake. However, the
aim of Kamphuis et al., (2003) was to observe the effect that
CLA has on regaining weight after a weight loss programme
with a very-low-calorie diet. The majority of the studies were
parallel clinical trials (Table 1), but in some cases the study
design was a crossover (Table 2; Tricon et al., 2004; Petridou
et al., 2003; Desroches et al., 2005). The intervention studies
were of differing lengths, most of them (n = 18) between 4 and
13 weeks. Two of the studies selected were more long term: the
study by Gaullier et al. (2004) took 52 weeks and the one by
Whigham (2004) took 28 and 52 weeks. In 2005, Gaullier et al.,
published an extension to their 2004 study. They administered
3.4 g CLA/day for 144 weeks. The results of this study were
very similar to those reported in 2004, but because there was no
placebo group they have not been included here.
Composition of the CLA Preparations Administered
and the Placebo
The first studies were carried out with mixtures of CLA iso-
mers whose percent composition were not well defined (Gaullier
et al., 2004; Benito et al., 2001; Kreider et al., 2002; Zam-
bell et al., 2000). Subsequent studies used mixtures of CLA
that predominantly contained the trans10cis12 and cis9trans11
isomers in a proportion of 1:1, manufactured by Natural LTD
(Norway) and Loders Croklaan BV (Holland). Some authors
have used CLA preparations in which a single isomer pre-
dominates (Riserus et al., 2004; Benito et al., 2001; Kreider
et al., 2002; Noone et al., 2002; Tricon et al., 2004; Zambell
et al., 2000; Riserus et al., 2002a) or mixtures of isomers at dif-
ferent percentages (Blankson et al., 2000; Thom et al., 2001;
Malpuech-Brugere et al., 2004; Mougios et al., 2001; Riserus
et al., 2001; Smedman and Vessy, 2001; Wihgham et al., 2004).
Desroches et al. (2005) use butter naturally enriched to 80% with
the CLA isomer cis9trans11.
The amount of total CLA used in the clinical trials is between
1.4 and 6.8 g/day, a dose that is comparable to that used in exper-
imental animals if we take into account the amount administered
per unit of metabolizable energy. In most of the studies, CLA
is administered as free fatty acids, although in a few, it is ad-
ministered as triglycerides (Riserus et al., 2004; Gaullier et al.,
2004; Benito et al., 2001; Kamphuis et al., 2003; Malpuech-
Brugere et al., 2004). The studies were carried out by adminis-
tering capsules containing CLA-based preparations and making
comparisons with capsules containing placebos. The placebos
used were canola oil, olive oil, sunflower oil, soya oil, linoleic
acid, oleic acid, hydrogel, safflower oil, or butter with a low
content of CLA (Tables 1 and 2).
Effects on Weight and Body Composition
Of the 21 trials reviewed determining the evolution of weight,
20 observed no significant changes in body weight attributable
to the intake of CLA. Only Gaullier et al. (2004) observed a
significant change in body weight after CLA supplementation
for 12 months. In a subsequent study published in 2005 with
the same population, the same authors have shown that the body
weight lost during the first 12 months of supplementation was
maintained during a further period of 12 months of supplemen-
tation with CLA (Gaullier et al. (2005). The change in body
weight attributable to CLA, (corrected for the changes that oc-
cur in the control group) fluctuate between +0.24 kg in the study
by Zambell et al. (2000) and +2.0 kg in the study by Tricon et al.
(2004). In the study by Kamphius et al. measuring weight regain
after a highly hypocaloric diet, more weight was gained in the
group receiving CLA.
In 19 of the 21 studies selected, changes in body composition
were determined by direct or indirect methods: waist circum-
ference (Riserus et al., 2001), infrared analysis (Thom et al.,
2001), skin folds (Mougios et al., 2001; Smedman and Vessy,
2001; Petridou et al., 2003; Taylor et al., 2006; Moloney et al.,
2004), hydrodensitometry (Kamphuis et al., 2003), bioelectric
impedance (Riserus et al., 2004; Tricon et al., 2004; Berven
et al., 2000; Riserus et al., 2002a; Smedman and Vessby, 2001;
Wihgham et al., 2004), DEXA (Gaullier et al., 2004; Blankson
et al., 2000; Benito et al., 2001; Kreider et al., 2002; Zambell
 CONJUGATED LINOLEIC ACID INTATE IN HUMANS 483

Table 1 Parallel clinical trials included in the review

Effects on
Number of Body Mass
individuals Index Length of CLA dose Lean body Body composition Glucose metabolism
Author, Year (M/F) (kg/m2 ) intervention (g/day) CLA composition Placebo mass Fat mass method used Lipid profile and other effects

Blankson, 2000 52 (1735) 2535 12 weeks 1.76.8 50% trans10cis12, Olive oil NS Decrease DEXA NS No data
50% cis9ttrans11
Berven, 2000 47 (30/17) 27,539 12 weeks 3.4 50% trans10cis12, Olive oil NS NS Bioimpedance NS No effects on insulinemia
50% cis9trans11 or glycemia
Zambell, 2000 17 (0/17) about 22 64 days 3.9 22.6% trans10cis12, Sunflower oil NS NS Impedance and NS No data
17.6% cis9trans11 DEXA
Benito, 2001 17 (0/17) about 22 9 weeks 3.9 22.6% trans10cis12, Sunflower oil NS NS Impedance and NS No data
17.6% cis9trans11 DEXA
Mougios, 2001 24 (14/10) <30 4 weeks 0.7 or 1.4 51% trans10cis12, Soya oil No data NS Anthropometry NS No dada
49% cis9trans11
Riserus, 2001 24 (24/0) 2739 4 weeks 4.2 37% trans10cis12, Olive oil No data Waist Anthropometry NS No effects on insulinemia
36.9% cis9trans11 decrease or glycemia
Smedman, 53 (26/27) about 25 12 weeks 4.2 50% trans10cis12, Olive oil No data Decrease Anthropometry NS No effects on insulinemia
2001 50% cis9trans11 or glycemia
Thom, 2001 20 (10/10) <25 12 weeks 1.8 50% trans10cis12, Hydrogel No data Decrease NIR No data No data
50% cis9trans11
Kreider, 2002 23 (23/0) <25 4 weeks 6 22.6% trans10cis12, Olive oil NS NS DEXA No data No effects on insulinemia
17.6% cis9trans11 or glycemia
Noone, 2002 51(23/28) <25 8 weeks 3 50% trans10cis12, Linoleic acid No data No data No data NS
50% cis9trans11
<25 8 weeks 3 20% trans10cis12, Linoleic acid No data No data No data NS No effects on insulinemia
80% cis9trans11 or glycemia
Riserus, 2002 60 (60/0) 2739 12 weeks 3.4 35% trans10cis12, No data NS NS Bioimpedance Decrease in HDL NS
35.4% cis9trans11
2739 12 weeks 3.4 76,5% trans10cis12, No data NS NS Decrease in HDL Increase in glycemia and
2,9% cis9trans11 CRP, decrease in insulin
sensitivity
Kamphuis, 54 (26/28) 2530 13 weeks after 3 1.8 or 3.6 50% trans10cis12, Oleic acid Increase in NS Hydrodensitometry NS No effects on insulinemia
2003 weeks VLCD 50% cis9trans11 gain plus dilution with or glycemia
deuterium
CLA FFA
Gaullier, 2004# 180(31/149) 2530 12 months 3.4 41%trans10cis12, Olive oil Increase Decrease DEXA Increase in Lp(a) No effects on insulinemia
39%cis9trans11 or glycemia
CLA TG
2530 12 months 3.4 38%trans10cis12, Olive oil NS NS Increase in Lp(a)
38%cis9trans11
Malpuech- 81(4140) 2530 18 weeks 1.53 94%trans10cis12, Oleic acid-rich NS NS DEXA No data No effects on insulinemia
Brugere, 2004 94% cis9trans11 sunflower oil or glycemia
Riserus, 2004 25 (250) 2735 12 weeks 3 7.3% trans10cis12, Olive oil No data NS Impedance NS Decrease insulin
83% cis9trans11 sensitivity. No effect
onglycemia
Whigham, 52 (1735) 2735 52 weeks 6 37% trans10cis12, Oleic acid-rich NS NS Densitometry Decrease in HDL No effects on insulinemia
2004 37% cis9trans11 sunflower oil Increase in TG or glycemia
Moloney, 2004 32 About 30# 8 weeks 3.0 50% trans10cis12, Palm oil and No data NS Antropometry LDL:HDL ratio Increase fasting glucose
50% cis9trans11 soya bean oil increased and reduce insulin
sensitivity
Taylor, 2006 40 (400) >27 12 weeks 4.5 36% trans10cis12, Olive oil No data NS Impedance NS No effects on abdominal
35% cis9trans11 computed tomografhy
measurements, glycemia
or HOMA-IR.

All the trials determined body weight. Gaullier et al. (2004) were the only ones to observe a significant decrease in weight attributable to the consumption of CLA. VLCD = Very low
calorie diet.# Type 2 diabetic patients.
#
The original article by Gaullier et al. published in 2005 is an extension of the original study published by the same author in 2004 (Gaullier et al. 2004).

et al., 2002; Malpuech-Brugere et al., 2004) and computerized
tomography (Desroches et al., 2005; Taylor et al., 2006).
One of the clinical trials carried out on a small sample of
subjects observed a significant decrease in the waist circumfer-
ence attributable to CLA (Riserus et al., 2001). Four other trials,
involving a total of 305 subjects (of the 838 studied), observed
a significant decrease in the amount of total body fat (Gaullier
et al., 2004; Blankson et al., 2000; Thom et al., 2001; Smedman
and Vessby, 2001). This effect cannot be due to the administra-
tion of CLA in a higher dose than those studies that observe no
effect on fat mass or to the composition of the isomers admin-
istered. In two of the studies that observed significant effects of
484
Table 2 Crossover clinical trials included in the review
Effects on
Number of Body Mass Length of
individuals Index intervention CLA dose Lean body Body composition Glucose metabolism
Author, Year (M/F) (kg/m2 ) (type of study) (g/day) CLA composition Placebo mass Fat mass method used Lipid profile and other effects

2 consecutive 9
Petridou, 17 (0/17) < 30 weeks 2.1 g 50% trans10cis12, Soya oil NS NS Anthropometry NS No data
2003 (crossover) 50% cis9trans11
0.59
3 consecutive 8 1.10 7.8% trans10cis12,
weeks periods 2.38 79,3% cis9trans11 NS NS NS
(crossover)
Tricon, 2004 25 (25/0) 18-34 No placebo Impedance and No effects on insulinemia
0.63 anthropometry or glycemia
3 consecutive 8 1.26 84.1% trans10cis12,
weeks periods 2.52 10.6% cis9trans11 NS NS NS
(crossover)
Lower decrease
2 consecutive 8 in CT
Desroches, 16(16/0) > 26 weeks periods 2.39 CLA-enriched butter Butter low in No data NS# Abdominal TAC Increase in No data
2005 (crossover) 80% cis9trans11 CLA (0.24g) CT:cHDL
#Visceral or subcutaneous adipose area
 CONJUGATED LINOLEIC ACID INTATE IN HUMANS
CLA on the loss of total body fat (Blankson et al., 2000; Thom
et al., 2001), the nutritional intervention was associated to a
programme of physical exercise, which suggests that physical
exercise can amplify the effect on changes in body composition
(Terpstra, 2004). This greater effect on body composition of
CLA combined with exercise has also been recently reported in
mice (Bhattacharya et al, 2005).
Of the studies reviewed, only five directly determine the
amount of total body fat, and in all cases the method used was
DEXA. Two of these studies observed significant effects on the
loss of fat mass attributable to the consumption of CLA (Gaullier
et al., 2004; Blankson et al., 2000) while the effect observed in
the others was not significant (Gaullier et al., 2005; Kreider et al.,
2002; Malpuech-Brugere et al., 2004). In some studies (Gaullier
et al., 2004; Blankson et al., 2000; Thom et al., 2001), the net
loss of total body fat tends to be higher than the weight lost
during the study, indicating either that the lean mass increases
or that less lean mass is lost in the control group. In one of the
studies mentioned above a significant increase in the lean mass
was also observed (Gaullier et al., 2004).
As sustained weight loss is difficult to achieve, in 2003,
Kamphuis et al. studied the effects of a mixture of CLA on
body weight regain. They observed that the increase in regained
weight after a 3-week very-low-calorie diet was greater in the
CLA group than in the control group. They attribute this weight
gain to a greater increase in lean body mass.
We should point out that in two of the studies which find sig-
nificant effects on body fat, some authors belong to the company
that supplies CLA (Blankson et al., 2000; Thom et al., 2001), so
there may be some conflict of interest.
Effects on the Lipid Profile
Of the 21 articles selected, only 6 describe changes in the
lipid profile, some of which are non-beneficial. One describes
an increase in Lp (a) (Gaullier et al., 2004) attributable to CLA
being consumed as free fatty acids; another two describe a signif-
icant decrease in HDL cholesterol levels (Riserus et al., 2002a;
Whigham et al., 2004); and Whighams study (2004) also ob-
serves a significant increase in triglycerides attributable to the
CLA consumption. HDL cholesterol levels decrease not only af-
ter consumption of a mixture of the CLA isomers trans10cis12
and cis9trans11 (Riserus et al., 2002a; Wihgham et al., 2004) but
also after the intake of the single isomer trans10cis12 (Riserus
et al., 2002a).
None of the studies selected have observed significant ef-
fects attributable to CLA intake on the concentrations of total
cholesterol or LDL-cholesterol. However, Smedman and Vessy
(2001) observed a significant increase in LDL- cholesterol lev-
els in the group receiving CLA, although the changes observed
were not significantly different from the changes that took place
in the control group. The effect of CLA on lipid metabolism
may depend on the isomer selected. For example, in a recent
paper, Tricon et al. (2004) provided healthy men with three
different doses of cis9,trans 11-CLA or trans10,cis12-CLA.
485
Trans10,cis12-CLA supplementation increased triacylglycerol,
and both total and LDL-cholesterol concentrations more than
the cis9,trans11-CLA isomer.
Effects on Glucose Metabolism
Few studies have evaluated the effect of CLA intake on glu-
cose metabolism and insulin sensitivity in humans, but the data
available suggest that glucose metabolism may be negatively
affected by CLA isomers. In a placebo controlled study, Riserus
et al. (2001) observed a significant increase in glucose levels
both in the CLA and the control group. This increase, however,
was more pronounced in the control group, although not statisti-
cally significant. In another study by the same authors (Riserus
et al., 2002a), glucose levels increased significantly only in the
group receiving the isomer trans10cis12 and not in the case of
a mixture of different isomers. However, the increase was not
significantly different from that which occurred in the control
group. Smedman and Vessby (2001) also showed an increase
(p = 0.054) in glycemia after the consumption of a mixture of
CLA isomers (+2.5 mmol/L) in comparison with the control
group (1.3 mmol/L).
Smedman et al. (2001) observed no significant changes in
plasma levels of insulin after intake of a mixture of two CLA
isomers containing 0.7-2.0 g of trans10cis12. However, they did
observe that insulin levels tended to increase after an intake of
2 g of this isomer while in the control group they decreased.
Recently, Tricon et al. (2004) and Taylor et al. (2006) ob-
served no deleterious effects on glucose or insulin levels, or
sensitivity to insulin attributable to the consumption of dif-
ferent doses of CLA enriched with cis9, trans11 or trans10,
cis12.
It should be pointed out that Riserus et al., using the eug-
lycemic clamp technique, observed a significant decrease in in-
sulin sensitivity after intake of both trans10cis12-CLA (Riserus
et al., 2002a) and cis9trans11-CLA (Riserus et al., 2004).
Moloney et al. (2004) also showed that CLA supplementation
had an adverse effect on insulin and glucose metabolism in type 2
diabetic patients. CLA supplementation significantly increased
fasting glucose concentrations, and reduced insulin sensitivity
as measured by homeostasis model assessment or oral glucose
insulin sensitivity. In contrast, a decrease in plasma glucose con-
centrations was observed by Belury et al. (2003) in patients with
type 2 diabetes.
Effects of CLA on Lipid Peroxidation, Peripheral
Inflammation, and Endothelial Function
Several studies performed on healthy and obese subjects
have observed that CLA administration is associated with an
increase in some lipid oxidation and oxidative stress markers
or peripheral inflammation parameters. This effect is not re-
verted by vitamin E administration (Riserus et al., 2004; Riserus
et al., 2002a; Basu et al., 2000a; Basu et al., 2000b; Smedman
et al., 2004). Basu et al. were the first authors to observe that
486 J. SALAS-SALVADO ET AL.
the intake of some CLA isomers could induce lipid peroxida-
tion in humans (Wang and Jones, 2004a; Basu et al., 2000b)
They observed a significant increase in the urinary excretion of
8-iso-protaglandin F2 and 15-keto-dihydro-prostaglandin F2
(a marker for cyclooxygenase-mediated lipid peroxidation, and
thus an indicator of cyclooxygenase-mediated inflammation) in
both healthy subjects and patients with metabolic syndrome af-
ter they had consumed a 50:50 mixture of the CLA isomers
cis9, trans11 and trans10, cis12 for one to three months. Also
Smedman et al. (2004) observed that these urine markers in-
creased in healthy subjects after consuming a mixture of iso-
mers like the one mentioned above and, particularly, after con-
suming the isomer trans10, cis12 for 6 weeks. In 60 patients
with metabolic syndrome, Riserius et al. (2002b) observed an
increase of 578% in the urinary excretion of 8-iso-protaglandin
F2 (oxidative stress marker) in patients who took a mixture
of trans10, cis12 CLA for 12 weeks. This was accompanied
by an increase of 110% in the levels of C-reactive protein in
comparison with the placebo group and was related to the onset
of insulin resistance. Also in comparison to the placebo group,
Riserus et al. (2004) observed a significant increase in the ex-
cretion of 8-iso-protaglandin F2 (+50%) and 15-keto-dihydro-
prostaglandin F2 (+15%), markers of in-vivo oxidative stress
and inflammation, respectively, after the intake of isomer cis9,
trans11.
In a placebo controlled clinical trial with CLA, Moloney et al.
measured several peripheral inflammatory markers in type 2 dia-
betic patients. Unlike the studies mentioned above, CLA supple-
mentation significantly reduced fibrinogen concentrations and
had no effect on plasma CRP or IL-6. Recently, a significant in-
crease in CRP has been reported in subjects receiving a mixture
of the cis9,trans11 CLA and trans10,cis12 CLA (Smedman et al.,
2005). Nevertheless, this study has not reported any changes in
other inflammation parameters (TNF-, TNF- receptors and
vascular cell adhesion molecule-1) due to CLA supplementa-
tion (Smedman et al., 2005).
Finally, Taylor et al. (2006) recently found that a mixture of
CLAs significantly impaired brachial artery endothelial function
in 40 overweight healthy individuals, consistent with an adverse
impact on cardiovascular risk. CLA intake has not been reported
to make any significant changes in lipid profile, HOMA-IR or
plasma glucose or CRP.
In conclusion, human studies on how CLA affects body com-
position and metabolism are not consistent. Because there is no
sufficient evidence to demonstrate that the intake of CLA has a
positive effect on weight and body composition in humans, and
because of the possible undesirable effects on lipid or glucose
metabolism, lipid oxidation and endothelial function, further
randomized clinical trials, controlled with placebo, in large sam-
ples of patients in the mid/long term are required if the effects
and the safety of the intake of conjugated linoleic acid isomers
are to be clarified. Furthermore, the mechanisms underlying the
possible undesirable effects of CLA on glucose and lipid human
metabolism, which have not been described in animals, need to
be explored in the future.
ACKNOWLEDGMENTS
This study was partly funded by two grants from the Instituto
de Salud Carlos III, Red de Centros RCMN (C03/08), and Red
de Grupos (G03/140), Madrid, Spain.
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