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Department of Nutrition and Food Science, Auburn University, Auburn, AL 36849
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • protein restriction • food intake • body composition • leptin • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Deschepper and deGroote 1995
, Swick and Gribskov 1983
, White et al. 1994
and 1998
) or increased food intake
relative to body weight (Rothwell and Stock 1987
,
Zhao et al. 1996
). In contrast, some investigators have
found low-protein diets to depress food intake (Beck et al. 1989
, Mercer et al. 1994
). Menaker and Navia (1973)
observed that mature female rats offered a low-protein diet
ate amounts equal to those of rats fed an isocaloric normal-protein
diet. The reason for this discrepancy and the underlying mechanism of
the feeding response to low dietary protein is not clear.
Despite the controversy in food consumption in the rats fed
low-protein diets, a more consistent finding is an increase in body
fat content (Meyer 1958
, Noblet et al. 1987
, Russell et al. 1983
, Swick and Gribskov 1983
, White et al. 1994
and
1998
). It has been suggested that growing animals
restricted in dietary protein enhance their food intake in an attempt
to meet their protein requirement for lean tissue growth and as a
result, deposit excess energy as fat (Webster 1993
).
Hyperphagia caused by a reduction of dietary protein level is
accompanied by a decrease in food efficiency and an increase in energy
expenditure in an apparent attempt to dissipate excess energy
(Specter et al. 1995
). These changes in
metabolic efficiencies appear to be the result of adaptive
diet-induced thermogenesis associated with increased activity of
brown adipose tissue (Rothwell and Stock 1987
).
Recent findings have suggested that body fat is regulated by the
hormone, leptin, which is secreted from adipose tissue (Zhang et al. 1994
). Leptin is secreted into the blood in proportion to
the amount of body fat (Frederich et al. 1995
) and
transported across the blood-brain barrier by an
insulin-independent saturable system (Banks et al. 1996
). In the brain, leptin interacts with specific receptors
in the hypothalamus (Malik and Young 1996
). Exogenous
leptin decreases food intake by reducing meal size (Flynn et al. 1998
, Kahler et al. 1998
). In addition,
exogenous leptin appears to increase energy expenditure (Levin et al. 1996
, Sivitz et al. 1999
). Whether this
is an actual increase in energy expenditure or a prevention of the
decrease that normally accompanies a decrease in food intake is
currently being debated. The above has lead to the idea that leptin may
be a long-term regulator of feeding and body fat. Hyperphagia and
obesity induced by low dietary protein suggest that these rats either
have low circulating leptin concentrations, despite the elevation of
body fat, or are resistant to the effects of leptin. The latter is
supported by the finding that leptin resistance develops in rats made
obese by high-fat diets (Widdowson et al. 1997
).
The objectives of the present study were to examine the effects of various low levels of dietary protein on food intake, body composition and energy balance in rats and to relate these to the serum leptin concentration. We also examined serum ammonia and urea concentrations to assess peripheral signals of low dietary protein that may play a role in the regulation of food intake.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male, Sprague-Dawley rats (63) (Harlan, Indianapolis, IN) with an
initial body weight of ~150 g were randomly divided into seven groups
of nine. Each rat was housed individually in a wire mesh cage in an
environmentally controlled room (light on 0600–1800 h, 23 ± 3°C). Rats were given free access to diet and water. Body weight and
food intake (corrected for spillage) of each rat were recorded daily
throughout the experiment. All rats were adapted to a modified AIN-76
diet (Reeves 1989
) containing 20% casein for 5 d.
On d 6, one group of rats was killed by decapitation between 0800–1200
h, serving as a baseline control for the carcass composition analysis.
The diets of five of the groups were changed to one containing either
2, 5, 8, 10 or 15% casein. The remaining group continued receiving the
control diet containing 20% casein. All diets were isocaloric (16.3
kJ/g). The energy difference due to the variation of dietary protein
was compensated by an equivalent change of dietary carbohydrate. The
composition of the experimental diets is shown in Table 1
.
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After 2 wk, all rats were killed by decapitation between 0800–1200 h. Trunk blood of the rats was collected into chilled test tubes immediately after the decapitation. The blood was centrifuged at 1000 x g for 30 min at 4°C. The serum was stored in microcentrifuge tubes at -80°C. The gastrointestinal tracts were removed, and the epididymal and retroperitoneal fat pads were dissected. The weight of the fat pads and carcass (including both fat pads and the head) were determined. The carcasses were frozen for subsequent body composition analyses. All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee at Auburn University.
Determination of body composition.
Carcass composition analysis was performed according to the procedure
described by Harris and Martin (1984)
. Carcasses were autoclaved in
beakers covered with foil for 1 h at 120°C. Carcasses were
blended with 3 mL of distilled water/g body weight, and this mixture
was homogenized with a PowerGen 700 homogenator (Fisher, Norcross, GA).
Two sets of samples were taken in triplicate. One set was used to
determine the percentage of body water and ash. These samples were
dried in a forced draft oven for 2 d at 85°C and then were ashed
in a muffle furnace at 600°C overnight. The other set was used to
determine the percentage of body fat by chloroform/methanol extraction.
The percentage of protein was calculated by the difference. Total body
fat, protein, water and ash were determined by multiplying the ratio of
each component by the carcass weight. To calculate carcass energy and
energy intake, we assumed the energy content of protein and
carbohydrate to be 16.7 kJ/g and fat to be 37.7 kJ/g. From the baseline
control rats, the relationships between carcass components and body
weight were determined. Using these relationships and the experimental
animal’s body weight before the introduction of test diets, the
initial carcass composition of each rat was estimated. From the
difference between the final carcass composition and the estimated
initial carcass composition, the lipid gain, protein gain, energy gain,
energy efficiency (the ratio of energy gain to energy intake), protein
efficiency (the ratio of protein gain to protein intake), and energy
expenditure (the difference between energy intake and energy gain) were
estimated.
Determination of serum metabolites.
Serum protein was determined by a commercial kit based on the Bradford assay (Bio-Rad, New York, NY). Serum ammonia and urea nitrogen concentrations were determined by spectrophotometry using commercial colorimetric assay kits (Sigma, St. Louis, MO). The ammonia assay was based on the conversion of 2-oxoglutarate to glutamate by glutamate dehydrogenase. The urea nitrogen assay was based on the breakdown of urea to ammonia by urease and the subsequent conversion of phenol to indophenol by sodium nitroprusside. Serum leptin levels were determined with an RIA kit (Linco, St. Charles, MO), using an antibody raised against rat leptin.
Statistical methods.
Statistical analyses were performed with the computer program,
SuperANOVA (Abacus Concepts,, Berkeley, CA). Daily food intake and body
weight data were analyzed by a one-factor ANOVA with repeated
measures. Hormone, metabolite and energy balance data were analyzed
with a one-factor ANOVA. When a significant difference existed
among treatment groups, the Fisher’s protected least significant
difference post hoc test was employed. Some data were transformed prior
to the ANOVA to ensure homogeneity. Log values were calculated for
energy gain, energy gain from lipid, energy expenditure, and serum
leptin concentrations. Simple linear regression was performed between
protein intake and protein gain, total food intake and serum urea
nitrogen concentrations, serum leptin concentrations and carcass lipid,
and between serum leptin concentrations and energy gain derived from
fat. A difference with P 
0.05 was considered
significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, F5,48 = 15.8, P < 0.0001). Most
of the differences in food intake occurred during wk 1. During this
period, rats increased food intake with moderate protein restriction,
but decreased food intake with more severe restrictions. Lowering
dietary protein from the standard 20% casein to 15% caused an
increase in daily food intake (P = 0.005). Lowering the
level of dietary protein to 10% casein, further increased food intake
(15% vs. 10%, P < 0.0001). At 10% casein, daily
food intake was maximized. Though numerically lower, food intake in
rats fed 8% casein was not different from rats fed 10% casein
(P = 0.2). Lowering dietary protein further to 5%
casein resulted in a lower food intake than in rats fed 8% casein
(P = 0.02), but this was still greater than the
intake of rats fed the 20% casein diet (P = 0.003). Lowering dietary protein to 2% casein reduced food intake as
compared to the 20% casein fed controls (P < 0.0001). During wk 2, the food intake of all diet groups was not
different from the 20% casein controls, with the exception of the 2%
casein group, which continued to consume less food (P
< 0.0001). The differences in food intake among rats fed the
different low-protein diets can also be seen in their cumulative
food intakes (Table 2
).
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, F5,48 = 20.3, P
< 0.0001) No change in body weight was seen by decreasing dietary
protein from 20% casein to 15%, but thereafter, progressively
lowering the level of dietary protein resulted in a progressive
decrease in body weight.
Overall, the mean carcass weight of each group paralleled the mean of
their live body weight. Rats fed the 10% casein diet had lower carcass
weights than rats fed the 15% casein diet (Table 3
, P = 0.03). In general, lowering the dietary protein
level further resulted in a further decrease in carcass weight. The
lower carcass weight of the 10% casein group was due to a decrease in
body water (10% vs. 15% casein, P = 0.001; 10%
vs. 20% casein, P = 0.007). Neither body lipid,
body protein nor body ash of the 10% casein group was different from
that of the 15 or 20% casein groups. In rats fed the 8, 5 or 2%
casein diets, body protein progressively decreased, along with that of
body water, as the level of dietary protein was reduced. As opposed to
the general reduction in body protein and body water with lower amounts
of dietary protein, body lipid tended to increase. The exception to
this was the 2% casein group. In this group, the amount of body lipid
was lower than that of the 20% casein controls (P
= 0.02). The increase in the amount of body lipid with a decrease
in dietary protein appeared to plateau around 5%–8% casein. There
was no difference in body lipid content between these groups. The
amount of body lipid in the 10% casein group was lower than that of
the 5 and 8% casein groups (P 0.04) but still
tended to be greater than the 20% casein controls (P
= 0.06). The body fat in the 15% casein group was not different
from that of the 20% casein controls.
When body composition was expressed as a percentage of carcass weight, body protein tended to normalize across groups. Only the 5% casein group had a lower level of body protein relative to carcass weight than the 20% casein controls. Increases in percentage body fat due to low dietary protein were more exaggerated than absolute body fat content. For example, the 5% casein group had 38% more absolute body fat than the 20% casein group, but a 68% greater percentage body fat. Interestingly, percentage body fat of the 2% casein group was greater than that of the 20% casein group (P = 0.003), even though the absolute amount of body fat was lower.
Although rats fed various levels of low dietary protein had different
energy intakes, there was no significant difference in carcass energy
among the groups, except for the 2% casein group, which had lower
carcass energy than the other groups (Table 4
). Energy gain tended to be greater (P = 0.07) in
the 8% casein group than in the 20% casein group, though there were
no significant differences among the groups with the exception of the
2% casein group, which was lower than the other groups (P
0.01). However, there was a shift in energy partitioning
across the various levels of dietary protein. With the exception of the
2% casein group, carcass energy gain as lipid was inversely related to
level of dietary protein. In general, as the level of dietary protein
decreased, the greater the proportion of energy that was deposited into
carcass fat. Rats fed the 5% casein diet deposited more than twice as
much energy into fat as the control group (563 ± 58 kJ vs. 247
± 29 kJ, P = 0.0001). Conversely, as the
level of dietary protein decreased below 10% casein, so did the amount
of energy deposited into body protein. Rats fed the 5% casein diet
accumulated only 38% as much energy into protein as did rats fed 20%
casein (129 ± 17 kJ vs. 341 ± 15 kJ, P
< 0.0001). Energy efficiency did not differ among groups except
for a decrease in the 2% casein group. Energy expenditure, calculated
by the energy balance method, was ~11% greater in the 10% casein
group than the 20% casein control group (P = 0.007). Energy expenditures in other groups were not different from the
control group with the exception of the 2% casein group, which was
lower.
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. Between the 10% casein group and the 2% casein
group, the average amount of protein gain in the carcass decreased in a
linear fashion with the decrease in the average amount of protein
intake (r2 = 0.99, P
< 0.005). Protein gain was at a maximum in the 15 and 20% casein
groups. By extrapolating between the regression line (2–10% casein)
and a line drawn through the average of the 15 and 20% casein groups,
the break point where carcass protein gain begins to decrease with a
decrease in protein intake was estimated (see Fig. 2A
).
The break point was calculated to occur at 34.5 g of protein
intake over the 2-wk period. This amount of protein intake is
equivalent to consuming 12.5% casein diet for 2 wk and is an estimate
of the rat’s protein requirement. A similar pattern was seen when the
average serum protein concentration of the diet groups was plotted
against the level of dietary protein (Fig. 2B
). However,
in this case, the break point appeared at a slightly lower level of
dietary protein (10% casein). The mean serum protein concentration was
maintained in rats fed the 20, 15 and 10% casein diets, but decreased
in a linear fashion in groups fed diets lower than 10% casein. This
suggests that certain body proteins may be more sensitive to decreasing
amounts of dietary protein than are serum proteins. Alternatively it
may suggest that the protein requirement as calculated from the body
protein gain was overestimated. Overall, the current data suggested
that the protein requirement of the rats in this study was around
10–12.5% casein.
|
). The relationship between serum urea nitrogen
concentrations and the various levels of dietary protein is shown in
Figure 3B
. Serum urea nitrogen concentrations decreased
as the level of dietary protein decreased from 20% casein to 10%
casein (Fig. 3A
). Though the average concentration of
urea nitrogen was lower in the 5% casein group than in the 10% casein
group (P = 0.04), there was relatively little
change in the concentration of serum urea between the 10% casein group
and the 2% casein group. Serum ammonia concentrations were not
significantly different among the diet groups (data not shown).
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. When the data from the 2% casein group were excluded, a significant
inverse relationship was observed between the cumulative food intake
during the experimental period and serum urea nitrogen concentrations
(r2 = 0.19, P = 0.003) (Fig. 4A
). Interestingly, within the 2% casein
group, total food intake was also inversely correlated with the serum
urea nitrogen concentrations (r2 = 0.50, P = 0.02) (Fig. 4B
); however,
the slope was much greater within the 2% casein group (-30.4 vs.
-6.4), which resulted in there being no overall correlation between
these variables when all the data were plotted.
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). Epididymal fat pads of these rats did not show this
increase. Fat pad weights in the rats fed the 2% casein diet were
attenuated either to the level of the 20% casein controls
(retroperitoneal) or to a level smaller than the control (epididymal)
(Fig. 5A
). Serum leptin concentrations were greater in
the 5 and 8% casein groups and were lower in the 2% casein group
compared to the 20% casein controls (Fig. 5B
). The
other groups did not differ from controls. Serum leptin concentrations
were directly correlated with carcass fat
(r2 = 0.763, P < 0.001) (Fig. 6A
) as well as gain in carcass energy derived from fat
(r2 = 0.801, P < 0.001) (Fig. 6B
). Leptin, however, was not correlated
with cumulative food intake (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and Swick and Gribskov (1983)
.
Since food intake depends to an extent on protein content, this could
partially explain some of the discrepancy concerning
low-protein-induced feeding in the literature.
In diet selection experiments, young animals are able to match their
protein intake closely to their protein requirement and choose the
appropriate energy from protein (Leathwood and Ashley 1983
, Shariatmadari and Forbes 1993
). It has
been suggested that when the protein in the diet is restricted, food
intake is primarily determined by the animal’s attempt to meet its
protein requirement (Webster 1993
). If this is true, it
is reasonable that in our study, rats fed the low-protein diets ate
more than the control group (20% casein) to increase their protein
intake. However, despite the increase in food intake, the total protein
intake in these rats was still lower than that of the control group.
Meyer (1958)
proposed that excess energy intake limited further
increases in food intake by which the animal might obtain more protein
from a low-protein diet. This idea suggests that the mechanisms
controlling protein intake and energy intake interact to control total
food intake. Considering the reduced food intake of the 2% casein
group and the attenuation of food intake of the 5% casein group
compared to the peak intake, it appears that the ability of rats to
increase food intake to help meet their protein requirement is limited
to a finite range of dietary protein. Why extremely low dietary protein
decreased food intake remains to be determined. Peng et al. (1974)
suggested that a low-casein diet causes imbalanced plasma and brain
amino acid patterns, which may override the protein-hunger
mechanism.
Contrary to food intake, carcass fat content remained maximized in the
5% casein group. This suggests, that besides an increase in food
intake, a redistribution of body energy away from body protein toward
body fat can also play a role in body fat accumulation with low dietary
protein. When dietary protein was severely decreased to 2% casein,
rats still had a higher percentage of body fat as compared to controls,
despite the decrease in the amount of fat. This indicates that body
protein and body water were affected to a greater degree by the severe
reduction in dietary protein than was body fat. The decrease in body
protein and body water also explains why body weights decreased with
low dietary protein, despite the general increase in body fat. Others
have also found that animals fed low dietary protein accumulate more
body fat than animals fed normal levels of protein (Meyer 1958
, Noblet et al. 1987
, Russell et al. 1983
, White et al. 1994
and
1998
). The response to low dietary protein varied in
individual fat pads. The retroperitoneal fat pad was more responsive to
the diet than the epididymal fat pad. Similar effects of diet have been
observed in a study by West et al. (1995)
.
While body fat increased in rats fed low-protein diets, body
protein decreased. In the 2, 5, 8 and 10% casein groups, the gain in
carcass protein was directly related to the protein intake. Carcass
protein gain appeared to reach a plateau when the total protein intake
during the experimental period was > 34.5 g. From this, we
estimated that the protein requirement was 12.5% casein. Serum protein
concentrations showed a similar trend as protein gain with a slightly
lower break point at 10% casein. These estimates (10–12.5% casein)
are consistent with the published protein requirements for maintenance
(5.0%) and growth (15.0%) for laboratory rats by the National
Research Council (1995)
. Interestingly, our estimates of
protein requirement are close to the dietary protein level with the
highest protein efficiency (10% casein) and to the level at which food
intake was greatest. Thus, it appears that the peak of
low-protein-induced feeding occurs at or just below the protein
requirements of rats. Since animals tend to regulate their protein
intake to help meet their protein requirement, factors that affect
protein requirement, such as age, strain, gender, physical activity and
physiological stress, would also be expected to influence
low-protein-induced food intake (Menaker and Navia 1973
,
Webster 1993
, West et al. 1992
).
Differences in these factors could also account for some of the
discrepancies in the literature concerning the food intake response to
low dietary protein.
It is of interest that, across the levels of low dietary protein used
in this study, the pattern of the feeding response was similar to the
pattern of efficiency of carcass protein gain (Fig. 3A
).
This may provide a clue as to a possible mechanism of low-protein
feeding. The peak of the feeding response appeared to occur around the
peak of efficiency of carcass protein gain. It is at this point that
the largest percentage of amino acids would be used for protein
synthesis. As a result, it is also at this point that the lowest
percentage of amino acids would be involved in transamination or
deamination reactions. Increasing the level of dietary protein above
this level would increase the intake of amino acids, without an
increase in body proteins. This would result in a greater level of
amino acid transamination and deamination. This is supported by the
increase in serum urea nitrogen concentrations in rats fed between 10
and 20% casein (Fig. 3B
). Decreasing the level of
dietary protein below the level at which efficiency of carcass protein
gain is maximized would again result in a greater level of amino acid
metabolism. This would be due to an increase in the degradation of
endogenous proteins. As the level of the limiting amino acid drops
below its requirement, endogenous body proteins would be degraded to
supply the limiting amino acid for the synthesis of more vital body
proteins. The increased breakdown of endogenous protein would supply
not only the limiting amino acid, but other amino acids would now be
available in relative excess. This would again result in an increase in
amino acid metabolism. This may be reflected in the fairly stable
concentrations of serum urea nitrogen in rats fed the 2–8% casein
diets. The fact that serum urea nitrogen concentrations were
maintained, despite decreases in dietary protein, suggests that level
of endogenous amino acid deamination was increasing. If the above is
correct, it suggests that alterations in feeding induced by low dietary
protein may be related to amino acid nitrogen metabolism, possibly in
the brain. The lower the level of amino acid transamination and
deamination reactions, the greater the food intake; the greater the
level of amino acid transamination and deamination reactions, the lower
the food intake. This potential relationship between amino acid
deamination and food intake is supported by the inverse relationship
between cumulative food intake and serum urea nitrogen concentrations
(Fig. 4)
. A dietary protein-induced alteration in the serum urea
nitrogen concentration need not have a direct effect on food intake.
The level of amino acid transamination and deamination reactions may
alter the production of other compounds which themselves could affect
food intake.
Serum leptin concentrations were directly related to body fat content
(r2 = 0.763, P < 0.001) as well as energy gain derived from fat,
(r2 = 0.801, P < 0.001) in rats fed diets varying in protein. This is in agreement with
the finding that serum concentrations of leptin reflect body lipid
content in high-fat fed mice (Frederich et al. 1995
). The fact the serum leptin concentrations are increased
in two different models of diet-induced obesity (i.e., high-fat
and low-protein) suggests that the increase is not a direct effect of
the diet, but rather to the secondary increase in body fat. Leptin is
proposed to be a feedback signal from fat that reduces food intake and
increases thermogenesis (Campfield et al. 1995
,
Halaas et al. 1995
, Pelleymounter et al. 1995
). This has led to the general concept that leptin is a
long-term regulator of energy balance. In the current experiment,
in spite of the enhanced body fat and serum leptin concentrations, rats
fed 5 and 8% casein diets consumed either more food than the control
group (wk 1) or the same amount of food as the control group (wk 2).
Moreover, rats fed the 5 and 8% casein diets did not have increased
energy expenditure, implying that obesity induced by low dietary
protein may be associated with leptin resistance. Leptin resistance has
been found in obese rats fed a high-fat diet (Widdowson et al. 1997
). In high-fat fed animals, saturation or a defect
of the leptin transport system across the blood-brain barrier may
contribute to the leptin resistance (Caro et al. 1996
,
Van Heek et al. 1997
). Since leptin resistance has the
potential to occur at several points in its signaling pathway
(Havel 1998
), it would be of interest to determine the
site of resistance in low-protein-fed rats and compare it to the site
of high-fat animals. Because human obesity is also characterized by
elevated circulating leptin concentrations (Caro et al. 1996
, Lonnqvist et al. 1995
), this model
of obesity appears relevant to the human condition. Therefore, rats fed
low-protein diets, with the rapid development of hyperphagia and
increased body fat, may be an important animal model of
diet-induced obesity in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by USDA/NRICGP #9704044.
Manuscript received March 22, 1999. Initial review completed June 22, 1999. Revision accepted November 16, 1999.
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