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Lipids
DOI 10.1007/s11745-015-4115-8
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REVIEW
Impact of Conjugated Linoleic Acid (CLA) on Skeletal Muscle
Metabolism
Yoo Kim1 · Jonggun Kim2 · Kwang‑Youn Whang2 · Yeonhwa Park1
Received: 22 September 2015 / Accepted: 16 December 2015
© AOCS 2016
Abbreviations
ACC Acetyl-CoA carboxylase
AMPK AMP-activated protein kinase
BMR Basic metabolic rate
CLA Conjugated linoleic acid
CPT Carnitine palmitoyltransferase
ERR Estrogen-related receptor
FOXO Forkhead box O
GLUT4 Glucose transporter type 4
IL-6 Interleukin 6
LPL Lipoprotein lipase
MEF2 Myocyte enhancer factor 2
MHC Myosin heavy chain
NFκB Nuclear factor kappa-light-chain-enhancer of
activated B cells
NRF Nuclear respiratory factor
PGC-1α Peroxisome proliferator-activated receptor γ
coactivator 1α
PPARδ Peroxisome proliferator-activated receptor δ
RMR Resting metabolic rate
SIRT1 Silent information regulator two protein 1
TAG Triglyceride
TNF-α Tumor necrosis factor α
UCP Uncoupling protein
Introduction
The presence of conjugated linoleic acid (CLA, conjugated
octadecadienoic acid) in milk was first reported in the 1930s,
but it was not until the 1980s that CLA was shown to be a
bioactive food component [1]. CLA is formed during the
biohydrogenation of linoleic acid to stearic acid by rumen
bacteria [2]. In addition, trans-11 vaccenic acid (another
metabolite of biohydrogenation) is known to be converted
Abstract Conjugated linoleic acid (CLA) has garnered
special attention as a food bioactive compound that pre-
vents and attenuates obesity. Although most studies on the
effects of CLA on obesity have focused on the reduction
of body fat, a number of studies have demonstrated that
CLA also increases lean body mass and enhances physi-
cal performances. It has been suggested that these effects
may be due in part to physiological changes in the skeletal
muscle, such as changes in the muscle fiber type transfor-
mation, alteration of the intracellular signaling pathways
in muscle metabolism, or energy metabolism. However,
the mode of action for CLA in muscle metabolism is not
completely understood. The purpose of this review is to
summarize the current knowledge of the effects of CLA
on skeletal muscle metabolism. Given that CLA not only
reduces body fat, but also improves lean mass, there
is great potential for the use of CLA to improve mus-
cle metabolism, which would have a significant health
impact.
Keywords CLA · Conjugated linoleic acid · Skeletal
muscle metabolism · Obesity · Lean body mass · Physical
activity
This manuscript is based on work presented at the 2015 AOCS
Annual Meeting.
* Yeonhwa Park
ypark@foodsci.umass.edu
1 Department of Food Science, University of Massachusetts,
102 Holdsworth Way, Amherst, MA 01003, USA
2 Division of Biotechnology, Korea University, Seoul 136-713,
Republic of Korea
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to cis-9,trans-11 CLA by Δ9-desaturase in the tissues [3].
Thus, the primary dietary sources of CLA are meats and
dairy products from ruminants, although the overall CLA
intake from food is not considered substantial [4]. It has been
reported that CLA content ranges from 0.34 to 1.07 % of the
total fat in dairy products, and 0.12 to 0.68 % in raw or pro-
cessed beef [4]. In the United States, the average daily intake
of CLA from food sources is 104–151 mg and 176–212 mg
for women and men, respectively [5]. Accordingly, studies
have reported serum CLA levels of approximately 20 μM, or
0.1 % of total fatty acids, in subjects with low dairy or meat
consumption [6, 7], and approximately 50 to 180 μM with
CLA supplementation of 0.8–3.2 g per day for 2 months [7].
There are at least 28 known CLA isomers. Among
them, the cis-9,trans-11 and trans-10,cis-12 isomers have
been the focus of studies on various biological effects of
CLA [8]. The cis-9,trans-11 isomer is a naturally predomi-
nant isomer, accounting for over 80 % of naturally occur-
ring CLA [4]. In addition to the cis-9,trans-11 isomer, the
trans-10,cis-12 isomer is found at very low levels in nat-
ural foods, but, when CLA is produced by chemical syn-
thesis, this isomer is formed in significant amounts [8–10].
Currently, most commercial CLA preparations comprise
almost equal amounts of cis-9,trans-11 and trans-10,cis-12
isomers, up to >90 % of total CLA, and these preparations
are referred to as CLA mixtures or 50:50 mixtures.
CLA contains a trans configuration, and as there are
known negative health issues associated with trans fat,
some clarification with regard to CLA and trans fatty acids
is warranted. The definition of trans fat labeling by the US
Food and Drug Administration (FDA) is “all unsaturated
fatty acids that contain one or more isolated double bonds in
a trans configuration” [11]. It is clear, therefore, that CLA is
excluded from "trans" fat product labeling, as it has a trans
double bond that is conjugated, not isolated. Furthermore,
in July 2008, the US FDA approved CLA mixtures for
GRAS (generally recognized as safe) status in specific food
categories, including fluid milk, yogurt, meal-replacement
shakes, nutritional bars, fruit juices, and soy milk. Thus, it is
expected that there will be an increase in CLA in foodstuffs,
resulting in increased CLA intake for human health benefits.
CLA and Body Composition
Since 1997, with the discovery of the effects of CLA on
body composition in a mouse model [12], numerous studies
in various mammalian models have reported the effects of
CLA supplementation on the modulation of body composi-
tion by reducing body fat and/or increasing lean body mass
[8–10, 13–16]. While most studies in CLA have focused
on the reduction of body fat, there is significant evidence
supporting a concurrent increase in lean body mass, body
proteins, or specific skeletal muscle mass [5, 8, 16, 17].
CLA was also confirmed to increase total protein content
(not only %) as a representation of lean mass in animals
[12]. Tables 1 and 2 summarize studies that have investi-
gated changes in body composition in rodents. Of the two
major isomers, the trans-10,cis-12 CLA isomer signifi-
cantly correlates with this effect [18–21]. Some researchers
have suggested that CLA supplementation causes re-parti-
tioning of the body composition, with fewer adipose depots
and greater lean mass [22]. This observation was further
supported in a pig model, where a CLA mixture fed to pigs
at levels between 0.25 and 2 % of their diet acted as a re-
partitioning agent to induce a reduction in back fat and an
increase in lean body mass [23–27].
To date, there have been approximately 100 human stud-
ies investigating the regulation of body fat by CLA, and
Table 3 summarizes only those in which changes in both
body fat and lean body mass were reported. Compared to
the results observed in animal models, CLA intervention
studies in humans has yielded less substantial and more
inconsistent results (Table 3). Among the clinical trials
investigating the effects of CLA on both body fat and lean
mass, five publications reported changes in both [28–32],
while two studies reported increases in lean body mass
with no effect on body fat [33, 34]. Schoeller et al. [35]
performed a meta-analysis of 18 independent clinical stud-
ies assessing the effect of CLA on lean body mass, and
concluded that CLA supplementation led to a relatively
rapid onset of increased lean body mass, although the total
increase was not remarkable (less than 1 %). This conclu-
sion is further supported by a study of CLA in a mouse
model [36], in which an increase in lean muscle mass pre-
ceded a reduction in fat mass. These observations suggest
a potentially significant role of the muscle in the effects of
CLA on body composition.
Mechanism of CLA‑Mediated Change in Body
Composition
Multiple mechanisms have been suggested to explain the
effects of CLA on body composition [16, 17, 37]. These
include CLA-mediated energy modulation, including
reduced energy intake and enhanced energy expenditure,
along with the inhibition of fat accumulation in adipose
tissue.
The balance between energy intake and energy expendi-
ture is important for proper weight regulation. Energy
intake is from the food consumed, while energy expendi-
ture is the sum of the basal metabolic rate (BMR), thermo-
genesis, and physical activity. First, with regard to CLA and
energy intake, some studies have demonstrated that CLA-
fed mice ate less food, whereas other studies have reported
inconsistent results (Tables 1, 2) [38–43]. However, some
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Table 1 Summary of mouse studies on conjugated linoleic acid (CLA) and body composition
References Mouse CLA supplementation ResultseMuscle metabolism
StrainaGenderbFormcDosage (%)dDuration BW BFM LBM Food intake Energy expenditurefBiomarkersg
Park et al. [12]ICR F + M Mixture 0.5 4 weeks – ↓ ↑ ↓ ↑ CPT
West et al. [51]AKR/J M Mixture 1.0–1.2 6 weeks ↓ ↓ –↓ ↑ EE/↓ RQ
DeLany et al. [146]AKR/J M Mixture 0.25–1.0 6 weeks ↓ ↓ ↑ –
Park et al. [36]ICR F Mixture 0.5 8 weeks – ↓ ↑ ↓
Park et al. [18]ICR F Mixture/c9t11/
t10c12
0.25–0.5 4 weeks ↓ by t10c12 ↓ ↑ ↓
Tsuboyama et al.
[65]
C57BL/6J F Mixture 1.0 5 months – ↓–↓ TNF-α/
↑ GLUT4
Park et al. [147]ICR M Mixture 0.1 4 weeks – ↓ ↑
Ohnuki et al. [53]ddY M Mixture 0.25–1.0 4 and 8 weeks ↓ ↓ –↑ Oxygen consumption
Peters et al. [73]PPARα-KO M Mixture 0.5 4 weeks ↓ ↓ ↑ ↑ CPT1/↑
UCP2
Park et al. [148]ICR F Mixture 0.3 2 weeks ↓– – ↓
Ntambi et al. [149]ICR F Mixture 1.0 4 weeks – ↓ ↑
Hayman et al.
[150]
BALB/c M Mixture 0.1–2.0 4 weeks ↓ ↓ ↑ ↔EE/↔VA/↔RER↔Oxygen
consumption
Warren et al. [151]C57BL/6N F c9t11/t10c12 0.5 8 weeks ↓ ↓ –
Chardigny et al.
[152]
ICR F + M c9t11/t10c12 1.0 6 weeks – ↓ ↑
Terpstra et al.
[153]
BALB/c M Mixture 0.5 6 weeks ↓ ↓ ↑ –↑ EE
Hargrave et al.
[154]
MH/ML M Mixture 0.5 8 weeks ↓ ↓ –↓
Park et al. [155]ICR M t10c12 0.5 3 weeks – ↓ ↑
Javadi et al. [156]BALB/c M Mixture 0.5 3 and 12 weeks ↓ ↓ ↑
Ohashi et al. [157]C57BL, KK,
KKAy
F Mixture 0.5 4 weeks ↓ ↓ – –
Javadi et al. [158]BALB/c M Mixture 4.0 5 weeks – ↓– – ↑ EE
Park et al. [159]ICR F Mixture 0.5 4 weeks – ↓ ↑ ↓
de Roos et al. [160]ApoE KO M c9t11/t10c12 2.1 12 weeks ↓ ↓ – –
Hargrave et al.
[161]
M Mixture 0.5 2 and 8 weeks ↓ ↓ –↓
Winzell et al. [162]C57BL/6J F Mixture 1.0 12 weeks ↓ ↓ ↑ –
Bhattacharya et al.
[163]
BALB/c M Mixture 0.5 14 weeks ↓ ↓ –↑ EE
Viswanadha et al.
[164]
CD-1 F t10c12 0.15/0.3 6 weeks – ↓–
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Table 1 continued
References Mouse CLA supplementation ResultseMuscle metabolism
StrainaGenderbFormcDosage (%)dDuration BW BFM LBM Food intake Energy expenditurefBiomarkersg
Park et al. [44]ICR F + M Mixture 0.5 4 weeks ↓ ↓ ↑ ↓
Rahman et al.
[165]
C57BL/6J F Mixture 0.5 8 weeks ↓ ↓ – –
Javadi et al. [166]BALB/c M Mixture 0.5 4 weeks ↓ ↓ – – ↑ EE
Park et al. [16]ICR M Mixture 0.5 4 weeks ↓ ↑
Hur et al. [167]N2KO F t10c12 0.5 12 weeks ↓ ↓ –
Andreoli et al.
[168]
CF-1 M Mixture 0.3 4 weeks – ↓–
Halade et al. [97]C57BL/6J F Mixture/c9t11/
t10c12
0.5 6 months ↓ ↓ ↑ –
Moon et al. [169]ob/ob M Mixture 1.0 6 weeks ↓ ↓ ↑ –
Halade et al. [20]C57BL/6J F Mixture/c9t11/
t10c12
0.5 6 months ↓ ↓ ↑ –
Park et al. [55]129Sv/J F Mixture 0.5 4 weeks ↓ ↓ ↑ ↓ ↑ EE/↓ RQ ↑ CPT-1/↑
UCP2/↑
GLUT 4
Parra et al. [170]C57BL/6J M Mixture 3/10 mg/day 5 weeks ↓ ↓ – –
Halade et al. [171]C57BL/6J F Mixture/c9t11/
t10c12
0.5 6 months ↓ ↓ ↑
Park et al. [172]ICR M Mixture/c9t11/
t10c12
0.22/0.5 4 weeks – ↓ ↑ –
Fedor et al. [173]C57BL/6N F t10c12 0.5 4 weeks ↓ ↓ –
Scalerandi et al.
[174]
CF-1 M Mixture 1.0 4 weeks ↓ ↓ – –
a ApoE KO apolipoprotein E knockout; ddY Deutschland, Denken, and Yoken; MH high metabolic rate; ML low metabolic rate; N2KO nescient helix-loop-helix 2 gene knockout; PPARα-KO
peroxisome proliferator-activated receptor α knockout; SENCAR sensitive to carcinogenesis
b F female, M male
c Mixture, a mixed isomer of cis-9,trans-11 and trans-10,cis-12; c9t11, cis-9,trans-11 CLA isomer; t10c12,trans-10,cis-12 CLA isomer
d Dosage (%) denotes a designated weight percentage of CLA in diet
e BW body weight; BFM body fat mass; LBM lean body mass; – no change; ↑ increase; ↓ decrease. All changes are based on significant differences between or within groups as reported in
publications
f EE energy expenditure; RER respiratory energy ratio; RQ respiratory quotient; VA voluntary activity
g CPT carnitine palmitoyltransferase, GLUT4 glucose transporter type 4, IL-6 interleukin 6, TNF-α tumor necrosis factor alpha, UCP2 uncoupling protein 2, ↔ no change
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have suggested that the temporary reduction in food intake
as seen with a CLA-containing diet may be due to its palat-
ability when CLA is used as a free fatty acid. Moreover, in
a study using a pair-feeding comparison, changes in body
composition occurring with CLA were shown to be inde-
pendent of reduced food intake [44], and human clinical
trials showed no effect of CLA supplementation on food
intake [29, 30, 45–49]. These human studies all used self-
reported food intake methods, which calls into question
their validity [50]. Nevertheless, despite the lack of conclu-
sive evidence regarding the relationship between CLA and
dietary intake in humans, it is unlikely that the reduction in
food intake is the main mechanism of action for the change
in body composition seen with CLA.
Enhanced energy expenditure is one key to controlling
body composition. Several animal studies have suggested
that CLA increases overall energy expended [43, 51–58].
In clinical trials, CLA supplementation was shown to
Table 2 Summary of rat studies on conjugated linoleic acid (CLA) and body composition
a F female, M male
b Mixture, a mixed isomer of cis-9,trans-11 and trans-10,cis-12; c9t11, cis-9,trans-11 CLA isomer; t10c12,trans-10,cis-12 CLA isomer
c Dosage (%) denotes a designated weight percentage of CLA in diet
d BW body weight, BFM body fat mass, LBM lean body mass; – no change, ↑ increase; ↓ decrease. All changes are based on significant differ-
ences between or within groups as reported in publications
e TAG triglyceride
References Rat CLA supplementation ResultsdMuscle metabolism
Strain GenderaFormbDosage
(%)cDuration BW BFM LBM Food
intake
Energy
expendi-
ture
Biomarkerse
Stangl et al.
[22]
SD M Mixture 3.0 7 weeks ↓ ↓ ↑
Azain et al.
[175]
SD F Mixture 0.25/0.5 1, 5 and
7 weeks
–↓– –
Sisk et al.
[176]
Zucker M Mixture 0.5 5 and
8 weeks
– – –
Kim et al.
[177]
SD M Mixture 0.5-1.0 9 weeks – – –
Yamasaki et
al. [178]
SD M Mixture 1.5 3 weeks – ↓–
Henriksen et
al. [179]
Zucker F Mixture/
c9t11/
t10c12
0.42 g/day 3 weeks ↓ by Mix-
ture and
t10c12
↓ by
t10c12
–↓ protein
carbonyl/
↓ intra-
muscular
TAG /
↑ glucose
uptake by
Mixture
and
t10c12
Sanders et
al. [180]
Zucker F Mixture/
c9t11/
t10c12
0.42 g/day 3 weeks ↓ by Mix-
ture and
t10c12
– –
Botelho et
al. [181]
Wistar M Mixture 2.0 6 weeks – ↓ ↑ ↑
Ogborn et
al. [182]
Han:
SPRD-
cy
F + M Mixture 1.0/2.0 12 weeks – ↓–
Roy et al.
[183]
SD M Mixture 1.0 8 weeks – – –
DeGuire et
al. [184]
SD F + M Mixture 1.0 16 weeks – – –
de Almeida
et al. [185]
Wistar M Mixture 1.5 9 weeks – – –
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Table 3 Summary of human studies on conjugated linoleic acid (CLA) and body composition
References Subject CLA supplementation ResultsdEnergy expendi-
turee
Other comments
Characteristic GenderaFormbDose (g/day) Duration BW BFM LBM
Berven et al. [186]Overweight/obese F + M Mixture 3.4 12 weeks ↓– –
Blankson et al.
[114]
Overweight/obese F + M Mixture 1.7/3.5/5.1/6.8 6 and 12 weeks – ↓ 1.7, 3.4 and 6.8
at 12 weeks
↑ 6.8 at 12 weeks
Zambell et al. [63]Normal F Mixture 2.5 9 weeks – – – ↔ RMR/↔ REM
Kreider et al. [115]Normal/over-
weight
M Mixture 6.0 4 weeks – – –
Riserus et al. [187]Obese M Mixture/t10c12 3.4 12 weeks ↓ by t10c12 ↓ by Mixture and
t10c12
– Subjects with meta-
bolic syndrome
Kamphuis et al.
[28]
Overweight F + M Mixture 1.8/3.6 13 weeks – ↓ ↑ ↑ RMR Weight regain
Gaullier et al. [29]Overweight F + M Mixture (TAG/
Free form)
3.6/3.4 1 year ↓ ↓ ↑ ↑ EE Free-form increased
LBM/↓ food
intake
Malpuech-Buru-
gere et al. [47]
Overweight F + M TAG of c9t11 and
t10c12
1.5/3.0 18 weeks – – – ↓ Food intake
Riserus et al. [188]Obese M TAG of c9t11 3.0 12 weeks ↑– –
Gaullier et al. [45]Overweight F + M Mixture (TAG/
Free form)
3.6/3.4 2 year ↓ ↓ – 1-year extension
open study/↓ food
intake
Colakoglu et al.
[116]
Normal F Mixture 3.6 6 weeks ↓ ↓ ↑
Larsen et al. [189]Overweight/obese F + M Mixture 3.4 1 year – – – Weight regain/
hypocaloric diet
Pinkoski et al. [61]Unknown F + M Mixture 5.0 7 weeks ↓ ↑ ↔ RMR ↓ Protein degrada-
tion
Gaullier et al. [30]Overweight/obese F + M Mixture 3.4 6 months – ↓ ↑ ↔ Calorie intake
Lambert et al. [62]Normal/over-
weight
F + M Mixture 2.6 12 weeks – – – ↔ RMR ↔ Appetite
Laso et al. [190]Overweight/obese F + M Mixture 3.0 12 weeks – ↓–
Nazare et al. [59]Normal/over-
weight
F + M Mixture (TAG) 2.8 14 weeks – – – ↑ RMR ↓ Food intake
Steck et al. [33]Obese F + M Mixture 3.2/6.4 12 weeks – – ↑ ↔ RMR/↔ RQ
Tarnopolsky et al.
[117]
Normal/over-
weight
F + M Mixture 5.4 + 5 g creatine
mono-hydrate
6 months – ↓ ↑ Co-supplementation/
aging study model
Watras et al. [48]Overweight F + M Mixture 3.2 6 months ↓ ↓ –↑ RMR ↔ Energy intake
Diaz et al. [118]Overweight/obese F Mixture 1.8 + 0.4 mg cre-
atine picol-inate
12 weeks – – – Co-supplementation/
premenopausal
Park et al. [191]Overweight/obese F + M Mixture 2.4 8 weeks ↓– – ↓ Food intake
Sneddon et al. [34]Normal/obese M Mixture 2.3 + 1.3 g ω-3
fatty acid
12 weeks ↑–↑Co-supplementation/
crossover design
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a F Female, M male
b Mixture, a mixed isomer of cis-9,trans-11 and trans-10,cis-12; c9t11, cis-9,trans-11 CLA isomer; t10c12,trans-10,cis-12 CLA isomer; TAG, triglyceride form; Free form, free fatty acid form
c Green tea, standardized for 45 % epigallocatechin gallate and 90 % polyphenol; BCAA, branched-chain amino acid
d BW body weight, BFM body fat mass, LBM lean body mass; – no change, ↑ increase, ↓ decrease. All changes are based on significant differences between or within groups as reported in pub-
lications
e EE energy expenditure, RER respiratory energy ratio, RMR resting metabolic rate, RQ respiratory quotient, ↔ no change
Table 3 continued
References Subject CLA supplementation ResultsdEnergy expendi-
turee
Other comments
Characteristic GenderaFormbDose (g/day) Duration BW BFM LBM
Norris et al. [192]Obese F Mixture 6.4 16 weeks ↓ ↓ – Type 2 diabetes/post-
menopausal
Raff et al. [31]Normal/over-
weight/obese
F Mixture/c9t11 5.5/4.7 16 weeks – ↓ by Mixture ↑ by Mixture Postmenopausal
Cornish et al. [46]Obese F + M Mixture 4.3 + 9 g cre-
atine mono-
hydrate + 36 g
whey protein
5 weeks – – ↑ ↔ Energy intake
Racine et al. [32]Overweight/obese F + M Mixture (TAG) 2.4 7 months ↓ ↓ ↑ Childhood model
Joseph et al. [193]Overweight/obese M Mixture/c9t11 2.8/2.7 8 weeks – – – Crossover design
Chen et al. [119]Overweight/obese F + M Mixture 1.7 12 weeks ↓ ↓ –
Macaluso et al.
[126]
Normal/over-
weight
M Mixture 4.8 3 weeks – – – Crossover design/
serum testoster-
one ↑
Lopez-Plaza et al.
[194]
Overweight F + M Mixture 3.0 24 weeks ↓ ↓ –
Shadman et al.
[195]
Overweight F + M Mixture 2.4 + 100 IU/day
vitamin E
8 weeks – – – Co-supplementation/
type 2 diabetes
Ormsbee et al.
[196]
Overweight/obese F + M Mixture CLA + Green
tea + BCAAc
8 weeks ↓– – Co-supplementation
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increase BMR (as resting metabolic rate, RMR) [28, 48,
59, 60], although other studies found no influence of CLA
on BMR, regardless of changes in body composition [33,
61–63].
As part of the increased expenditure of energy, CLA sup-
plementation may increase thermogenesis, as evidenced by
the upregulation of uncoupling proteins (UCPs) expressed
in various tissues, such as the adipose, liver, and the skel-
etal muscle in mice and rats [38, 40, 55, 56, 64–66]. UCP1
through UCP5 are mitochondrial proteins involved in the
combustion of stored or excess energy into heat. They are
expressed in distinct tissues in the body, and are responsible
for adaptive thermogenesis. Thus, an increase in UCPs by
CLA suggests that CLA may increase energy expenditure
by enhancing thermogenesis [67]. Likewise, physical activ-
ity also contributes to the overall expenditure of energy.
Studies in rodents have reported that CLA supplementation
increased energy expenditure in part by increasing the level
of physical activity [43, 56, 68], although human studies
are inconsistent in this regard [59, 61, 69].
In addition, fatty acid β-oxidation may contribute to
reducing body fat mass by using fat as an energy source,
rather than storing it in the body. Increased fat oxidation
in CLA-fed animals has been reported, as measured either
by reduced respiratory quotient or by increased activ-
ity and/or the expression of carnitine palmitoyltransferase
1 (CPT-1) in the skeletal muscle [12, 21, 41, 55, 56, 68,
70–74]. Intriguingly, Close et al. [60] reported that human
subjects who received supplements with 4 g of CLA mix-
ture for 6 months had significantly increased fat oxidation
and energy expenditure during sleep. In another study,
CLA was found to potentiate adipocyte apoptosis, reduce
fat uptake, and/or modulate adipokine production, all of
which collectively contributed to the effective reduction
of fat accumulation [17]. At the same time, CLA increased
lean mass, which is an important observation, suggesting
that CLA targets skeletal muscle metabolism. The potential
effects of CLA on skeletal muscle metabolism, however,
have been less investigated.
CLA and Skeletal Muscle Metabolism
Skeletal muscle typically accounts for nearly 40 % of total
body mass, and acts as a significant regulator in overall
energy metabolism [75]. Muscle metabolism is a term used
to describe the complex biochemical reactions associated
with skeletal muscle function and development.
Overview of Muscle Energy Metabolism
The process of energy production for skeletal muscle is
tightly regulated by the type, intensity, and duration of
muscle exercise [76, 77]. Glycolysis is the catabolic pathway
for glucose in the cytosol under both anaerobic (absence of
oxygen) and aerobic (presence of oxygen) conditions. Aero-
bic glycolysis is an efficient means of producing adenosine
triphosphate (ATP) through mitochondrial oxidative phos-
phorylation, while anaerobic glycolysis produces an energy
supply with a much lower yield (36–38 ATPs produced by
aerobic glycolysis vs. 2 ATPs by anaerobic glycolysis). Dur-
ing high-intensity exercise, anaerobic metabolic pathways
are important, as aerobic metabolism alone may not be
adequate to meet energy demands, especially when there is
insufficient oxygen supply [78–80]. In contrast, low-inten-
sity endurance exercise (requiring less than 60 % of maximal
oxygen uptake) such as jogging and swimming consumes
glucose and fatty acids as the primary energy sources dur-
ing the first hour, and then relies on stored intramuscular
and adipose tissue triglycerides for energy [81]. Thus it is
believed that prolonged endurance exercise is the more effi-
cient way to consume stored body fat.
Adaptive Responses of Skeletal Muscle
The skeletal muscle tissue also demonstrates metabolic
plasticity in response to altered external and internal condi-
tions, such as nutrient deprivation during fasting or calorie
restriction and contractile activity including exercise [82].
One of the adaptive responses of the muscle is the ability
to change the fiber type to meet energy demands. Muscle
fiber in humans is composed of three myosin heavy chain
(MHC) isoforms: MHC I, MHC IIa, and MHC IIx/d or IIb.
MHC I are slow-twitch type I fibers, which have greater
mitochondrial content, oxidative capacity, and resistance
to fatigue, using fatty acids as a main energy source. Fast-
twitch type II fibers (especially type IIb) are classified as
glycolytic fibers, since they use glucose and phosphocre-
atine as primary energy sources. Type IIa is an intermediate
type between type I and type IIb [83]. In response to exer-
cise, the skeletal muscle remodels its fiber type between
oxidative slow-twitch and glycolytic fast-twitch [84] in
correlation with the contractile properties and the physi-
ological and metabolic characteristics [85]. For example,
an endurance exercise triggers fiber type remodeling from
glycolytic fast-twitch to oxidative slow-twitch [84]. These
adaptations in the skeletal muscle are accompanied by an
increase in mitochondrial biogenesis, with the alteration
of mitochondrial volume (content per gram of tissue) and
composition (protein-to-lipid ratio in the inner mitochon-
drial membrane) [86].
Molecular Responses of Skeletal Muscle Metabolism
A number of regulators participate in the above-described
adaptive responses in skeletal muscle. Among them,
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AMP-activated protein kinase (AMPK) is the prime ini-
tial sensor of fuel and energy status in the skeletal muscle
(Scheme 1) [87]. An increase in intracellular AMP concen-
tration causes a shift to an increased AMP/ATP ratio, and
AMPK is then activated to provide the needed energy in
the cell. An activated AMPK deactivates acetyl-CoA car-
boxylase (ACC) by phosphorylation, inhibits the synthe-
sis of malonyl-CoA from two acetyl-CoAs, and results in
the activation of carnitine palmitoyltransferase 1 (CPT1), a
rate-limiting enzyme for fatty acid β-oxidation in mitochon-
dria. AMPK also induces metabolic changes including an
increase in glucose uptake by the induction of glucose trans-
porter type 4 (GLUT4), translocation in the skeletal muscle,
and a decrease in the rate of glycogen synthesis through
the phosphorylation of glycogen synthase [82]. Similar to
AMPK, sirtuin 1 (SIRT1, a conserved nicotinamide adenine
dinucleotide [NAD]+-dependent deacetylase) acts as a sen-
sor of metabolic stimuli (such as stress, starvation, or calorie
restriction) [88]. SIRT1 also regulates several transcriptional
factors (including protein 53, forkhead box O, and nuclear
factor κ-light-chain-enhancer of activated B cells, NFκB),
and is known to be involved in longevity [88]. Both AMPK
and SIRT1 may coherently mediate the response at the cellu-
lar level to the metabolic stimuli in the skeletal muscle [89].
Peroxisome proliferator-activated receptor γ coactivator
1α (PGC-1α), a downstream target of AMPK and SIRT1,
regulates several downstream transcription factors, includ-
ing peroxisome proliferator-activated receptor δ (PPARδ),
nuclear respiratory factor-1 and -2 (NRF), estrogen-
related receptor α (ERRα), and myocyte enhancer factor
2 (MEF2). These factors are important in initiating mito-
chondrial biogenesis and inducing fiber type transformation
in the skeletal muscle [90, 91]. Further support for the
significance of PGC-1α was provided in a study reporting
that ectopically expressing PGC-1α in the skeletal muscle
of transgenic mice induced the muscle fiber conversion of
glycolytic fast-twitch type II fibers into oxidative slow-
twitch type I fibers [92]. In a similar manner, the overex-
pression of PPARδ (a downstream regulator of PGC-1α)
resulted in the development of slow-twitch type I fibers
in skeletal muscle [93, 94]. The signaling cascade AMPK
to PPARδ via PGC-1α is an important metabolic pathway
involved in adaptive metabolism in the skeletal muscle.
As such, we have focused primarily on this pathway to
uncover the potential mechanism of CLA in skeletal mus-
cle metabolism.
Overall Effects of CLA on Skeletal Muscle Metabolism
Previous studies using mouse models have clearly sug-
gested that CLA is associated with a significant quanti-
tative increase in lean mass [12, 95]. In addition, CLA
supplementation up-regulates CPT1 and UCP2 from the
skeletal muscle, suggesting that an overall increase in
energy expenditure and fatty acid oxidation with CLA may
contribute to the reduction in fat accumulation [52, 56, 95,
96]. CLA has also been reported to prevent age-associated
skeletal muscle loss in aged rodents [19, 97]. The preven-
tive role of CLA in muscle is further supported by our
results in Fig. 1 with animals known to develop inactivity-
induced obesity with muscle dystrophy. When a cognate
of CLA (conjugated nonadecadienoic acid, known to have
biological effects similar to those of CLA) was given to
these animals, we observed an increase in voluntary activ-
ity and a reduction in body fat, as well as an increase in
muscle size, suggesting that this treatment may have pre-
vented muscle dystrophy typically associated with these
animals [56, 98].
Effects of CLA on Adaptive Muscle Responses
There is currently limited evidence demonstrating the role
of CLA in skeletal muscle metabolism [19, 21, 66, 99–
102]. Supplementation of 1.2–2.0 % CLA in the diet of
pigs was found to significantly increase expression levels
of oxidative slow-twitch type I fiber, but did not increase
the expression of glycolytic fast-twitch type IIb and IIx
fibers in the pig’s skeletal muscle [103]. However, fiber
type changes are dependent on the growth phase in pigs
[104]. Similarly, Parra et al. [100] observed no CLA effect
on PPARδ and muscle fiber change in mice. Given these
limited studies, it cannot be conclusively stated that CLA
promotes muscle fiber type transformation. However, along
with the observation that CLA is linked to improved max-
imum endurance capacity in mice, it is highly likely that
EXERCISE
AMP:ATP
PPAR
PGC-1
AMPK
Mitochondria
biogenesis
Lipid
metabolism
SIRT1
Fiber type
transformation
CLA
Scheme 1 Proposed mechanism of CLA on muscle metabolism.
AMPK AMP-activated protein kinase, CLA conjugated linoleic acid,
SIRT1 silent information regulator two protein 1, PGC-1α peroxi-
some proliferator-activated receptor γ coactivator 1α, PPARδ per-
oxisome proliferator-activated receptor δ (Used with permission of
UMass Amherst)
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CLA influences muscle fiber type transformation [21, 68,
105, 106]. The effect of CLA on physical activity is further
discussed below.
Effects of CLA on Molecular Responses of Muscle
Metabolism
Several studies have reported the effects of CLA on the bio-
chemical alteration of several molecular markers of mus-
cle metabolism [19, 21, 66, 99–102]. CLA treatment was
shown to activate AMPK in murine skeletal muscle cells
[107–110], which negatively regulated ACC and enhanced
fatty acid β-oxidation [107, 110]. One study reported that
the cis-9,trans-11 CLA isomer activated AMPK at lower
concentrations (~50 μM), while the trans-10,cis-12 isomer
gradually activated AMPK in a dose-dependent manner up
to 120 μM, and then plateaued [108]. However, the effect
of CLA on SIRT1 activity in the skeletal muscle is cur-
rently not known [109].
CLA treatment did not affect the activity of PGC-1α, a
primary regulator in mitochondrial biogenesis, even when
the mitochondrial content in the human skeletal mus-
cle cells was increased by CLA [101]. Similarly, CLA-
fed mice and rats demonstrated no significant differences
in PGC-1α compared to control groups [66, 100]. On the
other hand, CLA treatment significantly up-regulated
PGC-1α in murine skeletal muscle cells [109], support-
ing the contention that CLA supplementation significantly
up-regulates molecular biomarkers such as succinate dehy-
drogenase, cytochrome c oxidase, superoxide dismutase 2,
catalase, and glutathione peroxidase in the skeletal muscle,
which is related to increased ATP production and thermo-
genesis via improved oxidative phosphorylation and anti-
oxidative capacity in the rodent models [19, 66]. These
results suggest that further confirmation is needed as to
whether CLA treatment is associated with mitochondrial
biogenesis through PGC-1α. Thus, further investigation is
required, particularly in humans, for a better understand-
ing of the correlation between CLA supplementation and
muscle fiber type transformation. In addition, CLA—in
particular, trans-10,cis-12—increased PPARδ expression in
murine muscle cells and mice [21, 102]. While these results
suggest that CLA may target muscle metabolism, no mech-
anistic studies have been completed to determine whether
CLA directly or indirectly influences any of these molecu-
lar targets.
Effect of CLA on Physical Activity
Animal studies using CLA and exercise are summarized
in Table 4. Studies using mice showed consistent effects
of reduced body fat or increased lean mass. Moreover,
there was a significant improvement in the exercise out-
come with CLA treatment (Table 4) [21, 68, 105, 106,
111]. Specifically, Kim et al. [21] reported that the trans-
10,cis-12 isomer was responsible for this effect, but not
the cis-9,trans-11 isomer. This is consistent with the role
of the trans-10,cis-12 isomer as the active isomer in body
fat reduction [18]. In contrast, studies in rats observed no
additional or synergistic effects of CLA treatment and exer-
cise training on endurance capacity and lean body mass
[43, 112]. This discrepancy was previously recognized as
Fig. 1 A cognate of CLA, conjugated nonadecadienoic acid (CNA),
significantly prevented muscle dystrophy in animals with inactivity-
induced obesity. a The data show that CNA supplementation (light
gray bars) resulted in a reduced number of smaller muscles (less than
700 μm) and increased number of medium-sized muscles (between
1500 and 2100 μm) compared to controls (black bars). b CNA-fed
animals had significantly increased average muscle size compared to
Nhlh-2 knockout controls. *Significantly different at P < 0.05. Six-
week-old female Nhlh-2 KO mice were fed either a control or CNA-
containing diet (0.1 % w/w of diet) for 8 weeks [semi-purified pow-
der diet, TD07518 (Teklad; Harlan Laboratories/Envigo, Madison,
WI, USA) with "vitamin-free" tested casein to avoid the naturally
occurring CLA in casein was used]. The diet consisted of an AIN-93-
based diet with 20 % fat total as soybean oil. The thigh muscle, vas-
tus lateralis, was frozen in liquid nitrogen, and frozen muscles were
cut into 10-μm section using a Cryotome. The sections were stained
with hematoxylin and eosin in order to visualize the muscle, and
muscle size was measured (>500 fibers) with ImageJ software (NIH).
Numbers are mean ± S. E (n = 3)
Lipids
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a consequence of the greater sensitivity of mice than of
rats to CLA, partly due to differences in the administered
CLA dose on a weight basis and/or differences in the phys-
iology of animals (in particular, male rats continuously
gain weight, and no significant effects of CLA have been
reported for body fat) [113].
There are currently 17 CLA human intervention studies
reporting on CLA with exercise, as summarized in Table 5.
Table 4 Summary of studies using conjugated linoleic acid (CLA) and exercise regimen in animals
a F female, M male
b Mixture, a mixed isomer of cis-9,trans-11 and trans-10,cis-12; c9t11, cis-9,trans-11 CLA isomer; t10c12,trans-10,cis-12 CLA isomer
c Dosage (%) denotes a designated weight percentage of CLA in diet
d BW body weight, BFM body fat mass, LBM lean body mass; – no change, ↑ increase, ↓ decrease. All changes are based on significant differ-
ences between or within groups as reported in publications
e EE energy expenditure, RER respiratory energy ratio, ↔ no change
f CPT1 carnitine palmitoyltransferase 1, LPL Lipoprotein lipase, PPARδ peroxisome proliferator-activated receptor δ, UCP2 uncoupling protein
2
References Animal CLA supplementation ResultsdExercise
type
Muscle metabolism Exercise
outcome
Strain GenderaFormbDosagecDuration BW BFM LBM Energy
expendi-
turee
Biomark-
ersf
Mizunoya
et al. [68]
BALB/c
Mice
M Mixture 0.5 % 1 week – ↓– Endurance
(swim-
ming and
running)
↓ RER
↑ Fat
oxida-
tion
↑ LPL ↑
Bhattacha-
rya et al.
[57]
BALB/c
Mice
M Mixture 0.4 % 14 weeks ↓ ↓ ↑ Endurance
(running)
↔ EE
Di Felice
et al.
[197]
ICR Mice M Mixture 0.425 mg/
day
6 weeks – ↑Endurance
(running)
↑ Muscle
hyper-
trophy
Banu et al.
[198]
C57BL/6
Mice
F Mixture 0.5 % 10 weeks ↓ ↓ ↑ Endurance
(running)
Zhang et
al. [199]
ICR Mice M Mixture 0.5 % 18 weeks ↓Endurance
(swim-
ming)
↔
Kim et al.
[105]
BALB/c
Mice
M Mixture 1.0 % 10 weeks ↓Endurance
(running)
↑
Kim et al.
[21]
129 Sv/J
Mice
M c9t11/
t10c12
0.5 % 6 weeks ↓ ↓ ↑ Endurance
(running)
↑ CPT1/↑
UCP2/↑
PPARδ
↑ by t10c12
Hur et al.
[111]
ICR Mice F Mixture 1.0 % 6 weeks ↓ ↓ Endurance
(running)
↑
Barone et
al. [106]
BALB/c
Mice
M Mixture 0.5 % 6 weeks ↓ ↑ Endurance
(running)
↑ Testos-
terone
↑
Shen et al.
[200]
129 Sv/J
Mice
M t10c12 0.1 % 7 weeks ↓ ↓ Endurance
(running)
Mirand et
al. [201]
Wistar
Rats
M Mixture/
c9t11/
t10c12
1.0 % 6 weeks – – – Endurance
(running)
Faulcon-
nier et al.
[202]
Wistar
Rats
M Mixture/
c9t11/
t10c12
1.0 % 6 weeks – ↓Endurance
(running)
Mirand et
al. [43]
Wistar
Rats
M Mixture/
c9t11/
t10c12
1.0 % 6 weeks – ↑ by
Mix-
ture
Endurance
(running)
Salgado et
al. [112]
Wistar
Rats
F + M Mixture 0.5 % 10 weeks ↓ ↓ ↑ Endurance
(swim-
ming)
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Among them, ten studies tested exercise outcomes [46,
61, 114–122]. Overall, the effect of CLA supplementation
on exercise outcome varied across studies; six reported
positive results [46, 61, 114, 116, 117, 120], while oth-
ers reported no difference [115, 118, 119, 121, 122]. Four
clinical trials evaluated the effect of CLA supplementation
on physical activity, without a regular exercise regime [30,
48, 123, 124]. Among them, one study reported improved
physical activity with CLA treatment over a period of
3 months [123]. In general, the studies were relatively
short-term in nature (with the exception of two, they were
less than 12 weeks in length), and thus no conclusion can
be drawn as to whether the lack of effect was due to the
limited supplementation periods or the ineffectiveness of
CLA.
Four studies in humans evaluated the effects of co-
supplementation of CLA with other supplements, such as
creatine monohydrate, chromium picolinate, whey protein,
or amino acids, along with exercise training [46, 117, 118,
125]. Two of these studies used CLA and creatine mono-
hydrate for short- (5 weeks) or long-term (6 months) dura-
tions, accompanied by resistance training, and reported
increased lean body mass and improved strength compared
to the control group [46, 117].
Interestingly, Macaluso et al. [126] conducted a clini-
cal trial to investigate the effect of CLA with resistance
training on serum testosterone levels. The authors reported
significantly increased serum testosterone and resistance
exercise capability with CLA supplementation, with no
significant change in body weight, fat mass, or lean body
mass. Others have reported that testosterone can improve
mitochondrial biogenesis and total energy expenditure, and
that CLA supplementation was found to promote endur-
ance capacity in trained mice via the upregulation of tes-
tosterone biosynthesis [106, 127]. Thus, it is possible that
CLA improves exercise outcome by modulating testoster-
one; however, the Macaluso et al. [126] study may have
been too short to have observed changes in body composi-
tion due to CLA. Generally, indications are that CLA may
influence muscle metabolism, but mechanistic studies are
currently lacking.
Potential Health Concerns of CLA
Based on the results of animal and human studies, four
aspects of CLA supplementation are of concern: insulin
sensitivity, oxidative stress, maternal milk fat, and liver
function. These topics have been previously reviewed in
detail [5, 14, 15]. Among these potential health concerns,
the effects of CLA on glucose metabolism may affect the
potential role of CLA in skeletal muscle metabolism, and
effects are inconsistent in both animal and human studies.
However, evidence suggests that the long-term use of CLA,
particularly as a mixture of the two main isomers, will
likely have no adverse influence on glucose metabolism [5,
45, 128].
Other health concerns associated with CLA do not
directly involve the skeletal muscle metabolism, although
this aspect is important in understanding the health impact
of CLA. Reports of human studies have consistently
linked CLA supplements to increased oxidative markers,
particularly isoprostanes, but not to other biomarkers [5,
129, 130]. It has been suggested that CLA itself might be
metabolized to structurally similar isoprostanes that cannot
be distinguished from the isoprostanes used as oxidative
markers [131, 132].
CLA is known to reduce body fat, and CLA supplemen-
tation has been reported to significantly reduce milk fat,
particularly in cows [133, 134]. A limited number of human
studies have reported none or minimal change in milk fat
content after short-term CLA supplementation (less than
5 days) [135–137], and in light of the primary difference
in milk fat origin between ruminants and humans, CLA is
expected to have minimal effects on human milk fat [133,
134]. The long-term effects of CLA on human milk fat
have yet to be determined.
In animal studies, there have been consistent obser-
vations of an enlarged liver with CLA feeding, but mini-
mal changes have been reported in human studies [8, 65,
138–142]. While it is likely that the effect of CLA on the
enlarged liver is specific to rodents, three human cases of
hepatitis have been associated with CLA [143–145]. Thus,
close monitoring of CLA supplementation with regard to
the health of the liver will be important, particularly with
long-term use.
Conclusion
To date, most mechanistic studies of the effects of CLA
on body composition have focused on lipid metabo-
lism in the adipose tissue. At the same time, a growing
number of studies have highlighted the importance of
CLA with respect to skeletal muscle metabolism, with
effects including increased energy expenditure and
enhanced physical activity. However, mechanistic stud-
ies investigating the mechanism by which CLA modu-
lates skeletal muscle metabolism are very preliminary,
and further investigation of the mechanistic effects of
CLA on the skeletal muscle metabolism, including mito-
chondrial biogenesis and muscle fiber type transforma-
tion, is needed. We expect that knowledge of the effect
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1 3
Table 5 Summary of human studies determining effects of conjugated linoleic acid (CLA) and exercise
References Subject CLA supplementation ResultsdExercise type Muscle metabolism Exercise
outcome
Characteristic GenderaFormbDosagecDuration BW BFM LBM Energy
expenditureeBiomarkersf
Blankson et al.
[114]
Overweight/
obese
F + M Mixture 1.7/3.5/5.1/6.8 6 and
12 weeks
–↓ 1.7, 3.4 and
6.8 at 12
week
↑ 6.8 at 12
week
Standardized
training
↑
Thom et al.
[203]
Normal F + M Mixture 1.8 12 weeks – ↓Strenuous
Kreider et al.
[115]
Normal/over-
weight
M Mixture 6.0 4 weeks – – – Resistance ↔
Loeffelholz et
al. 2003
Overweight F + M Mixture 3.8 6 months – ↓Resistance
Colakoglu et al.
[116]
Normal F Mixture 3.6 6 weeks ↓ ↓ ↑ Endurance ↑
Pinkoski et al.
[61]
Unknown F + M Mixture 5.0 7 weeks ↓ ↑ Resistance ↔ RMR ↑
Adams et al.
[204]
Overweight/
obese
M Mixture 3.2 4 weeks – Resistance
Nazare et al.
[59]
Normal/over-
weight
F + M Mixture
(TAG)
2.8 14 weeks – – – Regular train-
ing
↑ RMR
Tarnopolsky et
al. [117]
Normal/over-
weight
F + M Mixture 5.4 + 5 g
creatine
monohydrate
6 months – ↓ ↑ Resistance ↑
Diaz et al. [118]Overweight/
obese
F Mixture 1.8 + 0.4 mg
chromium
picolinate
12 weeks – – – Endurance ↔
Cornish et al.
[46]
Obese F + M Mixture 4.3 + 9 g cre-
atine monohy-
drate + 36 g
whey protein
5 weeks – – ↑Resistance ↑
Michishita et al.
[125]
Normal/over-
weight
F + M Mixture 1.6 + 1.52 g
amino acids
12 weeks – – Resistance
Chen et al.
[119]
Overweight/
obese
F + M Mixture 1.7 12 weeks ↓ ↓ – Resistance
Macaluso et al.
[126]
Normal/over-
weight
M Mixture 4.8 3 weeks – – – Resistance ↑ Testos-
terone in
serum
↔
Bulut et al.
[205]
Overweight M Mixture 3.0 4 weeks – – – Endurance
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of CLA on muscle metabolism will help to elucidate the
preventive effects of CLA on obesity, along with current
knowledge of its effects on adipose tissue. This knowl-
edge will also support the potential application of CLA
in the prevention of age-associated muscle loss, such as
sarcopenia.
Acknowledgments The authors thank Ms. Jayne M. Storkson for
help preparing this manuscript and Dr. Deborah J. Good at the Vir-
ginia Polytechnic Institute and State University for providing Nhlh-2
knockout animals. This material is based on work supported in part
by the National Institute of Food and Agriculture, U.S. Department of
Agriculture, the Massachusetts Agricultural Experimental Station, and
the Department of Food Science under Project No. MAS00998 and
MAS00450. Yoo Kim was supported in part by the Charm Sciences
scholarship from the Department of Food Science, University of Mas-
sachusetts, Amherst. Dr. Yeonhwa Park is one of the inventors of CLA
use patents assigned to the Wisconsin Alumni Research Foundation.
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