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*
Departments of Animal and Dairy Science and
Foods and Nutrition, University of Georgia, Athens, GA 30602 and
**
Hill’s Science and Technology Center, Topeka, KS 66601
2To whom correspondence and reprint requests should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • conjugated linoleic acid • rats • adipose tissue • cellularity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The ability of CLA to prevent mammary and other tumors
in rodents was first identified in the mid-1980s (Pariza and Hargraves 1985
) and has been the subject of several reviews
(Belury 1995
, Ip et al. 1994
, Ip 1997
, Scimeca et al. 1994
). There are eight
potential isomers of CLA, but the cis 9, trans 11
and trans 9, cis 11 isomers are thought to be
active as potential antioxidant and anticarcinogenic agents (Lin et al. 1995
).
More recently, the ability of dietary CLA to reduce body fat has been
demonstrated in mice (DeLany et al. 1999
, Park et al. 1997
, West et al. 1998
) and pigs
(Dugan et al. 1997
). The cellular basis, i.e., whether a
change in cell size or number, for the reduction in fat pad weights was
not established. However, decreased triglyceride content in white
adipose tissue of rats fed CLA has been demonstrated (Yamasaki et al. 1999
), implying that CLA inhibits lipid filling of
adipocytes. Two recent studies have demonstrated an inhibitory effect
of CLA in vitro on proliferation of 3T3-L1 preadipocytes (Brodie et al. 1999
, Satory and Smith 1999
). One of
these studies reported that CLA also prevented preadipocyte
differentiation (Brodie et al. 1999
), whereas the other
reported that CLA stimulated lipid filling (Satory and Smith 1999
). Other work demonstrated that rat pups from dams fed CLA
during gestation and lactation exhibit improved feed efficiency
(Chin et al. 1994
). Although carcass composition was not
reported, it would be expected that the improved feed efficiency would
be associated with reduced fat mass.
With the availability of pure isomers of CLA, it has now been
demonstrated that the reduction in fat mass observed in vivo is
attributed in large part to the trans-10, cis-12
isomer of CLA (Park et al. 1999b
). The objective of the
present series of studies was to confirm the effect of CLA on fat mass
in the rat and to determine the in vivo effect on adipose cell size and
number. Mixed CLA products containing predominantly the
cis-9, trans-11 and trans-10,
cis-12 isomers were used in these studies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The protocols for these experiments were approved by the University of
Georgia Institutional Animal Care and Use Committee. Female
Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were
used in Experiments 1 and 2. In both experiments, rats were
individually housed in hanging wire mesh cages and maintained on a 12-h
light:dark cycle at 22 ± 2°C. Upon arrival, rats were
acclimated to individual cages for at least 2 wk and had unlimited
access to pelleted nonpurified diet (Rodent Chow 5001, Purina, St.
Louis, MO) and water. After this adaptation period, the experimental
diets shown in Table 1
were fed. Feeders that minimized spillage were used. Any spilled food
was recovered and weighed. Diets were based on the AIN-93
recommendations (Reeves et al. 1993
). Two sources of CLA
were used. A purified CLA product (Nu-Chek-Prep, Elysian, MN) was 97%
CLA as indicated by the manufacturer and was found to contain 42.6% of
the cis-9/trans 11 isomer, 45.6% of the
trans-10/cis 12 isomer and 8.7% of other CLA
isomers as determined by gas chromatography (GC). The second source of
CLA was a feed-grade CLA product (Natural Lipids, Hovdebygda,
Norway) reported to contain 55% CLA by the manufacturer. GC analysis
confirmed that the product contained 21.3% cis
9/trans 11, 25.4% trans 10/cis 12 and
10.6% of other CLA isomers. Other major fatty acids in the product
included 24.0% oleic acid, 7.7% palmitate, 5.4% linoleic acid and
4.5% stearic acid.
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The objective of this study was to examine the effect of 0.25 and 0.5%
of purified CLA and 0.5% of a feed-grade CLA on growth performance
and body composition. Growing female rats (n = 40;
initial weight 158 g) were assigned to one of the four
experimental diets shown in Table 1
. The purified CLA was assumed to
contain 100% "active" CLA, whereas the feed-grade product was
assumed to contain 55% "active" CLA and was added at 0.91% of the
diet. A representative group (n = 6) of rats were
processed at the beginning of the study for baseline tissue weights.
Rats were fed the experimental diets for 5 wk. Body weight and food
intake were monitored three times per week. On d 35, rats were sedated
with CO2 and decapitated. Trunk blood samples were obtained
and allowed to clot. Serum was obtained by centrifugation (1200 x
g for 15 min) and stored at -20°C. Serum samples were
assayed for triglycerides, urea nitrogen and nonesterified fatty acids
(NEFA), using commercially available kits [triglycerides (INT
336), urea (BUN 535), Sigma Chemical, St. Louis, MO; fatty acids
(NEFA-C), Wako Chemical, Dallas, TX]. Inguinal, parametrial and
retroperitoneal fat pads were dissected, weighed and stored at -20°C
for later determination of cellularity. Adipose cell size distribution
was determined in osmium-fixed cells as described previously
(Lee et al. 1994
, Mersmann and MacNeil 1986
). Duplicate 50-mg portions of tissue were fixed in osmium
tetroxide. Cell size distribution and number were determined using the
Coulter Counter (Coulter Electronics, Hialeah, FL). Cells with
diameters from 20 to 240 µm were counted.
Gastrocnemius and soleus muscle and liver were also dissected and
weighed. Chemical composition of the remaining eviscerated carcasses
was determined as described previously (Roberts et al. 1995).
Experiment 2.
The purpose of this experiment was twofold. One goal was to determine
the effects of CLA on fat pad weight and fatty acid profile in acutely
(7 d) and chronically (49 d) fed growing female Sprague-Dawley
rats. A second goal was to determine whether dietary CLA affected
energy metabolism. There were 10 rats per treatment group or a total of
40 rats in the study. Chronically fed rats (initial weight 120 g)
were obtained as weanling rats, whereas acutely fed rats were several
weeks older (initial weight 175 g) at the start of the feeding
trial and had body weights similar to those at the midpoint of the
study in the chronically fed group. Groups of 10 rats were fed control
or 0.5% CLA diets (Diets 1 and 3 in Table 1
). To determine the effect
of CLA on energy metabolism, the chronically fed rats were placed in
respiration chambers for indirect calorimetry for 2-d periods during wk
1 (d 6,7), 4 (d 27, 28) and 7 (d 48, 49) of the study. At the
termination of the studies, rats in both the acute and chronically fed
groups were sedated with CO2 and decapitated for collection
of serum. Tissues were collected and weighed as in Experiment 1.
Samples of the liver and retroperitoneal fat pad were homogenized for
fatty acid synthase activity (Roberts et al. 1994
) and
were frozen for later determination of fatty acid profiles. The
retroperitoneal pad was selected on the basis of the response to diet
seen in Experiment 1. Serum was analyzed for triglycerides and NEFA as
in Experiment 1.
Energy expenditure.
Twenty-four hour energy expenditure was measured using a computer-controlled indirect calorimeter with 10 open-circuit respiration chambers (Oxymax; Columbus Instrument, Columbus, OH). An infrared analyzer was used to measure the carbon dioxide concentration, and an Oxymax oxygen sensor battery was used to measure oxygen concentration. A mass flow controller measured the air flow. Average oxygen consumption, average carbon dioxide production, respiratory quotient (RQ) and average heat production after adjustment for metabolic body size (body weight in kg = W0.75) were then determined. Energy balance measurement was based on subtraction of heat production (energy expenditure) from digestible energy intake, assuming negligible energy losses as combustible gas and urine. Other variables such as chamber temperature, water lick counts and feeding activity counts were also recorded.
Fatty acid profile.
The fatty acid profile of adipose tissue and selected diet samples was
determined by GC with a flame ionization detector (Shimadzu gas
chromatograph, Model 14 A, Columbia, MD). Tissue (100 mg adipose) and
diet (1 g) samples were saponified and methylated in duplicate using
procedures described previously (Azain 1993
).
Heptadecanoic acid was used as an internal standard. Fatty acid methyl
esters in hexane were separated on a Supelcowax-10 fused capillary
column (60 m x 0.53 mm, 0.50 µm film thickness;
Supelco, Bellefonte, PA) under isothermal conditions. Column
temperature was 240°C, injector temperature was 250°C and detector
temperature was 260°C. Sample size was 0.5 µL and
helium was the carrier gas. Peak identification was based on known
standards, which included pure samples of cis-9,
trans-11 and trans-10,
cis-12 CLA (Matreya, Pleasant Gap, PA). Under these
conditions, the cis-9, trans-11 (and
trans-9, cis-11) isomer elutes after
linolenic acid (18:3 
9, 12, 15) and is followed by the
trans-10, cis-12 isomer (Ha et al. 1989
).
Data were analyzed using the General Linear Models procedure of SAS
(SAS Institute, Cary, NC). In Experiment 1, orthogonal contrasts were
used to compare the responses to 0, 0.25 and 0.5% CLA and separately
to compare the pure and feed-grade forms of the 0.5% CLA diets.
The effects of diet and duration of feeding on fat pad weights and
fatty acid profile in Experiment 2 were analyzed as a 2 x 2
design with main effects of time (7 vs. 49 d) and diet (0 vs.
0.5% CLA). However, because initial body weight was different between
acutely and chronically fed rats, the effects of time on the response
to diet in the two groups were not compared directly. Results are
reported as least squares means ± pooled SEM.
P-values of 
0.05 were considered to be significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Overall, there was no effect of CLA on food intake or growth rate
(Table 2
). There was no effect of CLA on liver, heart, kidney, gastrocnemius or
soleus weights. Retroperitoneal and parametrial pad weights were
significantly lower in rats fed 0.5% pure or feed-grade CLA. The
reduction in fat pad weights with no difference in intake suggests a
specific effect on lipid metabolism and not a secondary response to a
reduction in energy intake. The difference in pad weight was even more
striking when initial weights were considered. For example, the
parametrial pad weight in rats killed at the beginning of the trial was
0.62 ± 0.0.03 g. Thus, although there was a 25% reduction in the
absolute weight of the pad between control and 0.5% CLA groups, there
was a 44% reduction in the accretion rate of the pad (Control,
1.04 g vs. CLA 0.58 g net gain; pooled SEM =
0.15 g; P < 0.01). Similarly, the weight of the
retroperitoneal pad at the start of the study was 0.31 ± 0.03 g. The net growth of the retroperitoneal pad during the trial
was 0.37, 0.28 and 0.20 g in Control, 0.25 and 0.5% CLA groups,
respectively (pooled SEM = 0.04 g; P
< 0.01). There was a numerical reduction in inguinal pad weights
and no significant effect of diet on the rate of accretion in this fat
pad.
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. However, there were effects on cell size
distribution in the retroperitoneal pad (Fig. 1
). The effects of the feed-grade CLA were similar to those of the
purified form and are not shown in the figure. In general, the
percentage of cells in the 40–60 µm diameter range was
greater and the proportion of cells in the 80–240 µm
range was lower in tissue from rats fed CLA compared with controls.
Cells with mean diameters of 60–80 µm were not affected.
There was an overall decrease in average cell diameter. Similar size
distribution changes were observed in the inguinal and parametrial pads
(Table 2)
. Changes in average cell diameter were commensurate with
weight changes in the pads. Thus, the inguinal pad was least affected
and the retroperitoneal pad was most affected by dietary CLA.
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Experiment 2.
Rats in the acute feeding group were heavier initially and had lighter
final weights than the chronically fed group. There was a reduction in
growth rate in rats fed 0.5% CLA for 7 d (2.31 vs. 1.64 g/d,
P < 0.05). This was not observed in wk 1 in the
chronically fed group and was not seen in Experiment 1 (Table 3
). Food intake was not affected by dietary treatment. Circulating
triglycerides and cholesterol were not affected by diet. However, there
was a trend (P < 0.10) for greater free fatty acid
concentrations in rats fed CLA. There was no difference in liver weight
due to diet or duration of feeding. Both the retroperitoneal
(P < 0.05) and parametrial fat pads (P
< 0.005) were larger in the chronically fed than in the acutely
fed group (main effect of time). There was an effect of dietary CLA on
both parametrial (P < 0.001) and retroperitoneal pad
weights (P < 0.05), with no time x diet
interaction. Parametrial pad weights were 28 and 27% lower in rats fed
CLA for 7 and 49 d, respectively (P < 0.001). The
main effect of dietary CLA in the retroperitoneal pad was accounted for
by a 26% reduction in pad weight in rats fed for 7 d
(P < 0.05). There was no significant difference in
retroperitoneal pad weights between control and CLA-fed rats at
49 d.
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Fatty acid synthase activity in liver and adipose tissue, whether
expressed per unit of protein or per unit of tissue, was greater in the
chronically fed group than in the acutely fed group (P
< 0.01, Table 4
), but there was no effect of diet.
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) compared with that in the acutely fed group. This effect was likely
accounted for by dilution of polyunsaturated fatty acids (PUFA) with
the products of de novo lipogenesis. The reverse was observed with CLA
feeding, resulting in several diet x time interactions. Rats that
were chronically fed CLA had a lower proportion of monounsaturates and
a greater proportion of polyunsaturates than the corresponding acute
group. The two main CLA isomers (c9/t11 and
c10/t11) found in the diet are reported in the
table. Both isomers were detected in tissues from control rats, but
accounted for <0.5% of the fatty acids. There was an increase in
tissue CLA in response to feeding CLA and this appeared to be time
dependent. CLA level increased threefold after 7 d of feeding and
sixfold after 49 d of feeding. Dietary CLA prevented the decrease
in the relative abundance of linoleate and linolenate seen in control
rats over time.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). There was no
effect of CLA on body weight or intake in male mice, but there was a
trend for reduced body weight in females. Similarly, West et al. (1998)
reported 40–80% reductions in specific adipose tissue
depots in male mice fed 1% CLA. The retroperitoneal pad was most
responsive, whereas the epididymal showed the least response. At this
dose (1%), CLA resulted in reduced growth and intake. It was noted
that the decrease in adipose tissue was greater than would have been
accounted for by the reduced intake and growth rate. In support of
this, it was shown that mice fed CLA had increased energy expenditure.
Regional differences in responsiveness to CLA were also noted in the
present studies (Table 2
, 3)
, with the parametrial and retroperitoneal
pads responding more than the inguinal in Experiment 1, and the
parametrial pad responding more than the retroperitoneal in Experiment
2. These regional differences are most likely accounted for by
differences in accretion rates of these tissues during the trial
(Dijan et al. 1983
). The present results demonstrate that 0.5% dietary CLA reduces adipose tissue mass in rats and suggest that, at least under these conditions, the response in rats is less than that seen in mice. In both experiments reported here, the reduction in fat pad weight was on the order of 15–25%, and not the large 50–80% reductions reported in mice. Chemical composition of the carcass was not affected by diet. This is likely explained by the relative leanness of Sprague-Dawley rats (~8% carcass fat) and the sensitivity of the body composition analysis vs. that of determining the mass of a discrete fat pad.
It should be noted that in the mouse studies reported by West et al. (1998)
, 1% CLA was fed and that this level of CLA also
reduced food intake. Studies by Park et al. (1997
, 1999a
and 1999b)
examined the effect of 0.5% mixed CLA (Nu-Chek-Prep) in
mice and are thus comparable to those reported here. In those studies,
intake was similar in some experiments (Park et al. 1997
) and reduced in CLA-fed mice in others (Park et al. 1999a
). In all cases, the reductions in intake and
subsequently in body weight of mice fed 0.5% CLA were in the range of
5–10% below that of control groups, whereas the reductions in carcass
lipid were on the order of 50–60%. The effect of diet on the weight
of specific fat depots was not reported in that study.
DeLany et al. (1999)
demonstrated dose-dependent
reductions in carcass fat and specific depots in response to feeding
0.25–1.0% CLA to male mice. The effects of CLA were independent of
intake. As in the present work, the retroperitoneal pad was more
responsive to CLA than the inguinal pad. Feeding 0.5% CLA appeared to
result in a 15–20% reduction in retroperitoneal pad weight, whereas
feeding 1.0% CLA caused a 50% reduction. Carcass lipid was 24% lower
in mice fed 0.5% CLA for 39 d than in the corresponding control
group. Reduced retroperitoneal pad weight was evident within 2 wk of
feeding 1% CLA (DeLany et al. 1999
).
The conclusion that reduced cell size can account for the effect of CLA
in vivo differs from the conclusion of in vitro experiments that found
a reduction in 3T3-L1 preadipocyte proliferation in the presence of CLA
(Brodie et al. 1999
, Satory and Smith 1999
). Because postweaning "growth" of adipose tissue
depots is accounted for in large part by lipid filling of existing fat
cells, the observation that the reductions in adipose tissue mass in
response to CLA can be accounted for by decreased cell size rather than
cell number is expected. The observation that triglyceride content
(mg/g tissue) of adipose tissue is reduced in CLA-fed rats is
consistent with decreased lipid filling (Yamasaki et al. 1999
). To determine whether there is an in vivo correlate to
the cell proliferation response, it would be necessary to expose
animals to CLA during fetal development when most preadipocyte
hyperplasia occurs (Faust et al. 1980
, Marques et al. 1998
).
Other studies have examined the metabolic effects of CLA on adipose
tissue and reported increased lipid mobilization, as evidenced by an
increase in lipolysis and glycerol release, and a decrease in lipid
deposition as evidenced by an decrease in lipoprotein lipase
(Park et al. 1997
). Similarly, dietary CLA has been
shown to reduce the concentration of fat in milk through an inhibition
of de novo lipogenesis in lactating dairy cows (Chouinard et al. 1999
, Loor and Herbein 1999). These changes in
lipid metabolism were found to be associated exclusively with the
trans-10, cis-12 isomer of CLA (Park et al. 1999b
). The cis-9, trans-12 isomer,
which is the more common natural form of CLA (Ha et al. 1989
, Lin et al. 1995
), appears to account for
the anticarcinogenic effects of CLA, but does not affect lipid
metabolism.
Changes in adipose tissue fatty acid profiles in response to CLA
feeding are consistent with an inhibition of desaturase activity
(Lee et al. 1998
). Adipose tissues from CLA-fed rats
had reduced palmitoleic and oleic acid (Table 5)
. There was no
significant difference in total percentage of saturated fatty acid, but
total PUFA were greater in CLA-fed rats. This was accounted for in
large part by an increase in the percentage of linoleic acid,
particularly in the chronically fed group. Although the decrease in
monounsaturated fatty acids is consistent with other reports
(Lee et al. 1998
), the increase in linoleic acid has not
been reported consistently. Hayek et al. (1999)
saw no
change in linoleic acid content of liver lipids of mice fed 1% CLA,
but an increase was noted in milk fat of dairy cows fed CLA
(Chouinard et al. 1999
). Differences in fatty acid
profile in response to CLA may relate to the type and amount of lipid
used in diets supplemented with CLA.
In contrast to what has been reported in CLA-fed mice (West et al. 1998
), there was not a significant difference in heat
production in rats fed CLA compared with controls. In agreement with
the mouse data, however, a decrease in the RQ or respiratory exchange
ratio was observed at d 27 and 28, but as with CLA-induced changes
in adipose tissue mass, the magnitude of the change was not as great as
that reported in mice (West et al. 1998
). The decrease
in RQ may be accounted for by an increase in lipid oxidation, which is
also supported by a trend for more circulating fatty acids in
CLA-fed rats (Table 3)
. There was no effect of CLA on gas exchange
or heat production in adult female pigs (Muller et al. 1999
).
A change in fat pad mass without a significant change in body weight,
body composition, feed intake or heat production is likely accounted
for by the sensitivity of the various assays. The lack of a significant
effect of CLA on chemical composition of the rats may have been due to
the relative leanness of the rats used and the sensitivity of the body
composition assay. The reduction in fat pad weights for three discrete
depots is a more precise measure than determination of lipid content of
carcass homogenates. The difference in total pad weights between
control and 0.5% CLA groups (Table 2)
, which amounts to ~0.9 g of
tissue, represents a 1 kJ/d difference in energy intake over the course
of the 35-d feeding period, if one assumes that the difference is
entirely lipid. Intake was not different between treatment groups and
averaged 15.4 g/d or 261 kJ/d (diet energy = 17.0 kJ/g). Thus, the
decrease in intake needed to account for the reduction in fat pad mass
observed is <1% of energy intake. Similar calculations can be made to
explain the lack of significant difference in the energy metabolism of
rats fed CLA.
In conclusion, the results of these studies demonstrate that the
reduction in adipose tissue mass in response to dietary CLA is
accounted for by a decrease in cell size rather than a change in cell
number. This basis for the reduction in fat pad mass is consistent with
metabolic changes (decreased lipid deposition and increased lipolysis)
reported previously (Park et al. 1997
, 1999a
and 1999b
).
The results suggest that rats are less sensitive to CLA than mice and
that there is no significant effect on heat production. There is a
time-dependent increase in tissue levels of CLA, but it appears
that the reduction in adipose mass is evident in as little as 1 wk of
feeding CLA. The observation that 7 d of feeding CLA was
sufficient to reduce fat pad weight (Experiment 2, Table 3
) differs
from results in mice, which suggest that several weeks are necessary to
detect a change in fat mass (Park et al. 1999a
).
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FOOTNOTES |
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3 Abbreviations used: CLA, conjugated linoleic acid; GC, gas chromatography; NEFA, nonesterified fatty acids; PUFA, polyunsaturated fatty acids; RQ, respiratory quotient.
Manuscript received September 30, 1999. Initial review completed December 20, 1999. Revision accepted March 3, 2000.
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