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* Department of Animal Sciences, Oregon State University, Corvallis OR 97331 and
Hill's Pet Nutrition, Inc., Topeka, KS 66601
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2, CCAAT/enhancer binding
protein 
and adipocyte specific protein 2 mRNA. CLA inhibited cell
proliferation of nonconfluent cells but did not affect cell division of
confluent cells, as indicated by 5-bromo-2'-deoxyuridine incorporation
and mitochondria metabolism. Therefore, CLA inhibited differentiation
before confluence and during induction. However, cellular proliferation
was only inhibited prior to induction. These results imply that fat
reduction caused by CLA treatment may be attributed to its inhibition
of both proliferation and differentiation of preadipocytes in
animals.
KEY WORDS: • adipocytes • conjugated linoleic acid • differentiation • proliferation • fatty acids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), reducing the
development of atherosclerosis (Lee et al. 1994
),
stimulating the immune system (Cook et al. 1993
) and
inducing enzyme changes in mouse liver (Belury et al. 1997
, Cantwell et al. 1998
).
Another effect of CLA could have a profound impact on human health and
animal production. Limited reports exist of CLA lowering body fat while
not affecting total body mass. Pigs fed CLA deposit less subcutaneous
fat, are leaner and show improved feed conversion efficiency
(Dugan et al. 1997
). Mice fed a CLA-supplemented diet
develop lower quantities of body fat and increased carnitine
palmitoyltransferase activity (Park et al. 1997
,
Chin et al. 1994
). Mature, cultured 3T3-L1 cells treated
with CLA have reduced lipoprotein lipase activity and reduced
intracellular concentrations of triacylglycerol and glycerol
(Park et al. 1997
). Therefore, the reduction of body fat
by CLA in vivo could be due to reduced fat deposition and increased
lipolysis in the adipocytes.
These results prompted the natural supplement industry to market CLA to humans (e.g., Peak Nutrition, Willington CT, and PharmaNutrients, Lake Bluff, IL). The promotional literature states that by consuming CLA, body fat can be reduced. One preliminary clinical study performed by PharmaNutrients indicates that after a 90-d period, CLA consumption reduced body fat by an average of 20%. With minimal information available regarding both the mode of action of CLA in reducing animal body fat and regarding the action upon humans, more basic information is necessary to protect consumers from possible detrimental effects.
As 3T3-L1 cells are a reliable system for analyzing the development of
adipocytes, we chose this system to study the effect of CLA during
preadipocyte differentiation. Although these cells are derived from
mice, the basic mechanisms for fat development appear to be similar in
both rodent and human cells (Mueller et al. 1998
). The
studies presented here show that CLA functions in at least two
different ways to inhibit adipocyte development. Treatment with CLA
during the cell-proliferative stage inhibited cell number and decreased
5-bromo-2'deoxyuridine (BrdU) incorporation and subsequent
differentiation. Treatment of the 3T3-L1 cells with CLA at the time of
induction of differentiation (after cells reached confluence) did not
affect cell numbers but did inhibit differentiation. Our results
indicate the presence of two different mechanisms of action of CLA in
3T3-L1 cells. Therefore, the action of CLA with dietary supplementation
may vary depending upon the stage of development of the cell, i.e.,
dividing cells could be severely inhibited by CLA consumption, while
nondividing cells could be less impacted.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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3T3-L1 preadipocytes were cultured and induced to differentiate as
described (Chen et al. 1997
). In short, cells were
placed into culture (d -6) and grown to confluence (d -2) before
induction (d 0). Terminal differentiation occurred by d 12. Cells were
treated with CLA, mixed isomers of 9,11, purity >99%, in dimethyl
sulfoxide (DMSO) (Nu-Chek-Prep, Inc., Elysian, MN) and linoleic acid
(LA, 9-cis, purity >99%, in DMSO, Nu-Chek-Prep, Inc.) at
the concentrations and times indicated.
Oil Red-O staining.
Cells were stained with oil Red-O and hematoxylin as described by
Suryawan and Hu (1993)
.
Northern analysis.
Total RNA was extracted from cells using the guanidinium-acid phenol
method (Chomczynski and Sacchi 1987
). RNA was separated,
blotted and probed with 18S as described in Brodie et al. (1996)
. Other blots were probed using DNA random prime labeled
with digoxigenin-dUTP as described by the manufacturer (Boehringer
Mannheim, Indianapolis, IN). Blots were prehybridized and hybridized at
50°C and washed two times at 50°C with 1X SSPE/0.1% SDS for 15 min
and one time with 0.1X SSPE/1% SDS at 60°C for 30 min. Detection was
performed as recommended by the manufacturer. Source of the probes:
18S, Dr. Stephen J. Giovannoni, Oregon State University; adipose P 2
(aP2), Dr. David A. Bernhohr, University of Minnesota; CCAAT/enhancer
binding protein (C/EBP), Dr. Stephen R. Farmer, Boston
University; peroxisome proliferator-activated receptor 2 (PPAR2),
Dr. Bruce Spiegelman, Dana Farber Cancer Institute.
Glycerol-3-phosphate dehydrogenase (GPDH) activity.
The GPDH (EC 1.1.1.8) assay was performed by a spectrophotometric
method for determination of the disappearance of NADH during
GPDH-catalyzed reduction of dihydroxyacetone phosphate under zero-order
condition (Kozak and Jensen 1974
) as modified by
Wise and Green (1979)
. The addition of CLA to the cells
1 h prior to the assay had no effect on GPDH activity. Protein was
measured according to Bradford (1976)
.
Cell number assay.
The colorimetric assay for quantitation of cell number and cell viability, based on the cleavage of the tetrazolium salt WST-1 {4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate} by mitochondrial dehydogenases, was performed according to the manufacturer (Boehringer Mannheim #1644 807).
5-bromo-2'-deoxyuridine (BrdU) incorporation.
After the indicated period of CLA treatment, cells were rinsed two times, and incorporation of BrdU was assayed after 2 h incubation, according to the kit supplied by Boehringer Mannheim (#1 647 229).
Statistical analysis.
Data were analyzed using the Students t-test to compare individual treatments to the DMSO-treated control cells.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).LA (50 and 100 µmol/L) treatment did not cause any inhibition (data
not shown). In addition to monitoring the GPDH activity, CLA-treated
and untreated cells were stained with oil Red-O to visualize the fat
(data not shown). After d 2, increases in the mRNA of two important
adipogenic transcription factors, PPAR2 and C/EBP, were inhibited
when CLA treatment began at d 0 (day of induction of differentiation,
Fig. 2
).In addition, aP2 mRNA, which is an indicator of adipocyte
differentiation, also did not reach control levels (Fig. 2)
. However,
these mRNA were not affected when CLA treatment began at either d 2 or
4 and continued through d 7 (data not shown).
|
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).Treating 3T3-L1 cells with CLA at different intervals before addition
of induction media (d -2 to 0) and during the presence of induction
media (d 0 to 2) resulted in inhibition of adipocyte differentiation
(Fig. 4
).
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showed that CLA
stops cells in the G0/G1 phase of cell growth, we determined the number
of cells present after CLA treatment. The tetrazolium salt WST-1
(4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene
disulfonate) is cleaved to formazan by enzymes that belong to the
respiratory chain of the mitochondria and is active only in viable
cells (see the Materials and Methods section). This assay was used to
determine the number of 3T3-L1 cells remaining after treatment with
CLA. We verified that WST is a reliable indicator of 3T3-L1 cell
numbers by comparing the actual number of cells to the amount of
formazan formed (data not shown). 3T3-L1 cells were treated with CLA,
either in normal growth medium or induction medium. Induction medium
was added to preconfluent cells to determine that this medium did not
interfere with the WST assay. The stage of cell growth influenced the
effect CLA had on cell number (Fig. 5
).Regardless of the medium, CLA treatment of preconfluent cells resulted
in lower cell numbers (Fig. 5A)
. However, confluent cells treated with
CLA were unaffected (uninduced cells), or the number was greater
(induced cells) (Fig. 5B)
.
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).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 and C/EBP
mRNA. Differentiation was inhibited by CLA treatment before and during
induction of differentiation. Cell proliferation was sensitive to CLA
inhibition only before confluence.
Although fatty acids stimulate adipogenesis (Amri et al. 1991
), our data indicate that CLA is an exception and is
inhibitory. For all variables measured, the LA-treated cells did not
differ from the DMSO-treated control cells. Initially, the BrdU results
indicated an inhibition of cellular proliferation by both CLA and LA,
even when more cells were clearly visible in the LA-treated cells (data
not shown). After several rinses to thoroughly deplete the media of the
fatty acids, only the CLA was inhibitory. The presence of the fatty
acid at the time of the addition of the BrdU may have inhibited BrdU
uptake.
The factors involved in adipocyte differentiation have been studied in
detail by numerous investigators (review: Mandrup and Lane 1997
). The first major gene induced by the induction hormones
during preadipocyte differentiation is C/EBPß (d 1 of culture)
(MacDougald and Lane 1995
). C/EBPß then induces
PPAR2 (d 2) and C/EBP (d 3). PPAR2 and C/EBP together
induces the expression of aP2. Downregulation of C/EBPß mRNA precedes
the upregulation of both PPAR2 and C/EBP. Therefore, both
PPAR2 and C/EBP mRNA should increase during the culture period to
induce adipocyte-specific genes responsible for fat accumulation (such
as GPDH and aP2). Our data (Fig. 2)
indicated that both C/EBP and
PPAR2 mRNA were indeed increased from d 2 to d 4 in the DMSO-treated
control cells. However, CLA treatment prevented both C/EBP and
PPAR2 mRNA from reaching the same level as the DMSO-treated
controls. Therefore, although the mRNA for PPAR2 and C/EBP in the
CLA-treated cells increase somewhat from d 0, the aP2 gene, which
requires PPAR2 and C/EBP, may not be maximally expressed when
these two transcription factors fail to reach the same levels as the
control cells. In cells treated from d 0 to d 7 with CLA, the mRNA of
PPAR2 and C/EBP again do not reach the levels seen in control
cells. This was reflected by the reduced mRNA level of aP2 that is
known to be regulated by PPAR2 and C/EBP. This indicates that CLA
acts by influencing this well-described pathway. However, when cells
are treated after induction (d 2), the mRNA of these three factors was
not affected.
Houseknecht et al. (1998)
showed that aP2 mRNA level was
increased in the epididymal fat pads from diabetic fatty rats treated
with CLA. Using a transfection study, they demonstrated that CLA and
troglitazone can activate PPAR transcription. They hypothesize from
these data that increased PPAR is responsible for increased aP2
mRNA. However, Okuno et al. (1998)
showed in vivo that
troglitazone does not increase the mRNA of PPAR in epididymal
adipose tissue. Therefore, even though Houseknecht et al. (1998)
demonstrated that CLA and troglitazone increased aP2
mRNA, no data exist to support that this is a result of PPAR
transcription in vivo. Confounding the interpretation of the data by
Houseknecht et al. (1998)
is the fact that they assayed
whole epididymal fat pads that include preadipocytes as well as mature
adipocytes. Having the adipocytes at two different developmental stages
leads to difficulty in interpreting their results.
In addition, fat depots are characterized by marked metabolic
differences, depending upon their location (Maslowska et al. 1993
). Raclot et al. (1997)
showed that
polyunsaturated fatty acids have different effects, depending upon the
fat site. Supplementation of Ob1771 and Ob1754 preadipose cells with LA
activates aP2 gene expression (Amri et al. 1991
). These
cells are also of epididymal origin, coming from the obese ob/ob adult
mouse (Smas & Sul 1995
). In another system,
PPAR2-expressing NIH 3T3 cells, LA induces expression of the aP2
mRNA, although LA is less effective than other PPAR activators
(Tontonoz et al. 1994
). Although we detected some
stimulation by LA, the effects were not significant. Apparently fat
cells from alternative sites and genetic background respond differently
to fatty acids.
Animals fed CLA have less body fat (Dugan et al. 1997
,
Park et al. 1997
). CLA reduced feed intake, improved
feed conversion efficiency, decreased subcutaneous fat and increased
lean deposition in pigs (Dugan et al. 1997
). Park et al. (1997)
concluded that the lower body fat and increased
lean body mass in mice fed CLA "appear to be due in part to reduced
fat deposition and increased lipolysis in adipocytes, possibly coupled
with enhanced fatty acid oxidation." Our data suggest that the
CLA-induced fat reduction in these animals could be attributed to its
effect on adipose hyperplasia. This does not exclude the possible
effect of CLA on adipocyte hypertrophy. More work is required to
determine the CLA effect on lipogenesis and lipolysis in mature
adipocytes.
Proliferation of MCF-7 human breast cancer cells is inhibited by CLA
treatment (Durgam and Fernandes 1997
). Cell cycle
analysis indicated that the CLA blocked MCF-7 at the G0/G1 phase, thus
reducing cell growth. Our results of CLA treatment of proliferating
cells could also be explained by a block at the G0/G1 phase. As the
3T3-L1 cells would be unable to reach confluence due to CLA inhibition,
there may be incomplete response to the induction media, resulting in
inhibition of differentiation.
CLA also exerts a dose-dependent reduction in proliferation of A-427, a
lung adenocarcinoma cell line (Schonberg and Krokan 1995
). A significant increase in lipid peroxidation is observed
with the inhibition. Although the formation of malondialdehyde, the
indicator of peroxidation, was completely abolished by the addition of
vitamin E, growth rates were only partially restored, indicating an
additional mechanism. Cantwell et al. (1998)
also
concluded that CLA may act as a prooxidant because they found that CLA
downregulated cellular antioxidant enzymes when hepatocytes were
exposed to oxysterols. This oxidative action of CLA may inhibit
differentiation of our 3T3-L1 cells.
Our study clearly identified an effect of CLA on proliferation and
differentiation. We did not measure fat accretion, and therefore we
cannot ignore the fact that CLA has affected lipogenesis or lipolysis.
However, treatment of the 3T3-L1 cells by CLA from d 4 to 7 did not
affect mRNA for PPAR2, C/EBP and aP2. In fact, Park et al. (1997)
showed that CLA has an additional effect on cells if the
CLA is added during fat accretion. They found that CLA added at d 4
after induction reduced lipoprotein lipase activity and enhanced
lipolysis, resulting in less fat deposition.
With supplements of CLA now available for human consumption, it becomes more imperative to understand how this fatty acid can affect hypertrophy and hyperplasia of fat cells. Our data demonstrate that CLA is an effective inhibitor of both preadipocyte proliferation and differentiation. Thus, CLA may prove to be a valuable feed supplement to control the deposition of fat in animal production.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This is Technical Paper #11337 of the Oregon
Agricultural Experiment Station.
2 K.R.F. was supported in part by a summer
undergraduate internship from the Research Office, Oregon State
University.
3 The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
5 Abbreviations used: aP2, adipose P 2; BrdU,
5-bromo-2'-deoxyuridine; C/EBP, CCAAT/enhancer binding protein ;
CLA, conjugated linoleic acid; DMSO, dimethyl sulfoxide; GPDH,
glycerol-3-phosphate dehydrogenase; LA, linoleic acid; PPAR2,
peroxisome proliferator-activated receptor 2.
Manuscript received June 4, 1998. Initial review completed July 8, 1998. Revision accepted November 16, 1998.
|
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 H. M. Roche, E. Noone, C. Sewter, S. Mc Bennett, D. Savage, M. J. Gibney, S. O'Rahilly, and A. J. Vidal-Puig Isomer-Dependent Metabolic Effects of Conjugated Linoleic Acid: Insights From Molecular Markers Sterol Regulatory Element-Binding Protein-1c and LXR{alpha} Diabetes, July 1, 2002; 51(7): 2037 - 2044. [Abstract] [Full Text] [PDF]
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 E. Rodriguez, J. Ribot, and A. Palou trans-10, cis-12, but not cis-9, trans-11 CLA isomer, inhibits brown adipocyte thermogenic capacity Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1789 - R1797. [Abstract] [Full Text] [PDF]
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S. P. Poulos, M. Sisk, D. B. Hausman, M. J. Azain, and G. J. Hausman Pre- and Postnatal Dietary Conjugated Linoleic Acid Alters Adipose Development, Body Weight Gain and Body Composition in Sprague-Dawley Rats J. Nutr., October 1, 2001; 131(10): 2722 - 2731. [Abstract] [Full Text] [PDF]
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J. M. Brown, Y. D. Halvorsen, Y. R. Lea-Currie, C. Geigerman, and M. McIntosh Trans-10, Cis-12, But Not Cis-9, Trans-11, Conjugated Linoleic Acid Attenuates Lipogenesis in Primary Cultures of Stromal Vascular Cells from Human Adipose Tissue J. Nutr., September 1, 2001; 131(9): 2316 - 2321. [Abstract] [Full Text] [PDF]
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 S. L Elias and S. M Innis Infant plasma trans, n-6, and n-3 fatty acids and conjugated linoleic acids are related to maternal plasma fatty acids, length of gestation, and birth weight and length Am. J. Clinical Nutrition, April 1, 2001; 73(4): 807 - 814. [Abstract] [Full Text] [PDF]
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L. D. Whigham, E. B. Cook, J. L. Stahl, R. Saban, D. E. Bjorling, M. W. Pariza, and M. E. Cook CLA reduces antigen-induced histamine and PGE2 release from sensitized guinea pig tracheae Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R908 - R912. [Abstract] [Full Text] [PDF]
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Y. Choi, Y.-C. Kim, Y.-B. Han, Y. Park, M. W. Pariza, and J. M. Ntambi The trans-10,cis-12 Isomer of Conjugated Linoleic Acid Downregulates Stearoyl-CoA Desaturase 1 Gene Expression in 3T3-L1 Adipocytes J. Nutr., August 1, 2000; 130(8): 1920 - 1924. [Abstract] [Full Text]
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M. J. Azain, D. B. Hausman, M. B. Sisk, W. P. Flatt, and D. E. Jewell Dietary Conjugated Linoleic Acid Reduces Rat Adipose Tissue Cell Size Rather than Cell Number J. Nutr., June 1, 2000; 130(6): 1548 - 1554. [Abstract] [Full Text]
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G. I. Stangl Conjugated Linoleic Acids Exhibit a Strong Fat-to-Lean Partitioning Effect, Reduce Serum VLDL Lipids and Redistribute Tissue Lipids in Food-Restricted Rats J. Nutr., May 1, 2000; 130(5): 1140 - 1146. [Abstract] [Full Text]
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 M. W. Pariza, Y. Park, and M. E. Cook Mechanisms of Action of Conjugated Linoleic Acid: Evidence and Speculation Exp Biol Med, January 1, 2000; 223(1): 8 - 13. [Abstract] [Full Text] [PDF]
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A. Brodie Response to Drs. Moya-Camarena and Belury J. Nutr., November 1, 1999; 129(11): 2106 - 2106. [Full Text] [PDF]
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