Plasma growth hormone secretion is impaired in obesity-prone
rats before onset of diet-induced obesity
Thomas J.
Lauterio1,
Ariel
Barkan2,
Mark
DeAngelo1,
Roberta
DeMott-Friberg2, and
Ray
Ramirez3
2 Medical Service, Department
of Veterans Affairs Medical Center, Ann Arbor, Michigan 48105; and
1 Departments of Physiology and
Internal Medicine and 3 Surgery,
Eastern Virginia Medical School, Norfolk, Virginia
23501
 |
ABSTRACT |
Sprague-Dawley rats, which become obese (obesity
prone) when fed a moderately high-fat (MHF; 32.5% of kcal as fat)
diet, have decreased growth hormone (GH) concentrations compared with
obesity-resistant rats fed the same diet. To determine whether plasma
GH concentrations are different in obesity-prone rats compared with
obesity-resistant rats before diet-induced obesity occurs, total
integrated GH concentrations were determined in male Sprague-Dawley
rats before exposure to the MHF diet. After initial blood sampling,
rats were fed an MHF diet for 15 wk, over which time the animals were
separated into two discrete populations based on body weight gain.
Analysis of GH in episodic blood samples showed that the obesity-prone
group had a GH secretion deficit before the onset of obesity (115.2 ± 12.9 ng · ml
1 · 200 min
1) compared with
obesity-resistant rats (237.2 ± 47.1 ng · ml
1 · 200 min
1). The GH
concentration difference was due to a decrease in mean GH peak height
in rats that later became obese (34.8 ng/ml) compared with rats that
remained lean (74.2 ng/ml). The results suggest that GH secretion
impairment exists before dietary challenge or onset of obesity and may
contribute to the susceptibility to obesity observed in these animals.
episodic growth hormone secretion; dietary fat
 |
INTRODUCTION |
OBESITY IS one of the most prevalent diseases in the
United States, affecting an estimated 25-35% of the population
(9, 17). However, factors that contribute to the susceptibility of the
disease are only recently coming to light. The task of identifying
causative or contributory factors is made more difficult because of the
multietiologic nature of obesity and the multiple metabolic
perturbations that occur in obese individuals.
Because it is difficult to study susceptibility to obesity in humans,
animal models have been utilized to acquire information that would not
otherwise be obtainable. These models include genetically obese animals
[Zucker rat, ob mouse
(34)], surgically induced obese animals [ventromedial
hypothalamus-lesioned rat (10, 33)], spontaneously
obese animals [rhesus monkey (6)], and diet-induced obese
rat and mouse (21, 29, 30, 46). However, perhaps the most relevant of
these models with regard to human obesity are those in which obesity
develops in response to increased dietary fat. In particular, the
dietary model originated by Levin et al. (29), which was later
developed into a purified diet (26), is of considerable interest
because it allows one to examine resistance and susceptibility to
obesity. In this paradigm, rats fed a moderately high-fat (MHF) diet
(32.5% of kcal as fat) diverge into distinct populations based on body
weight gain. Approximately one-half of the rats fed this diet will gain
weight rapidly compared with chow-fed or control (low fat) rats. The
remaining one-half, on the other hand, will gain body weight at a rate
that is equivalent to or lower than control fed animals. The former
group is referred to as obesity prone (OP), whereas those in the latter
group are referred to as obesity resistant (OR). Work in our laboratory has focused on characterizing this model with regard to the metabolic and endocrine status of OP and OR rats (26, 27).
One of the endocrine abnormalities observed in the diet-induced obese
model is decreased circulating levels of growth hormone (GH) in the
obese compared with the OR rats (27). This reduction in GH
concentration is also a consistent finding in obese humans (5, 14, 19,
25). The diet-induced obese rat also has a decreased somatotroph
response to growth hormone-releasing hormone (GHRH) (27), which
parallels the impaired response to GH secretagogues observed in human
obese individuals (13, 16, 24, 25). Because GH stimulates lipolysis (8,
11, 15, 41), it is feasible that lack of GH contributes to increased
adipose accumulation in obesity. However, it is not known when GH
concentrations change during the onset of obesity and what factors lead
to these changes. The animal model described above affords us an
opportunity to examine GH levels from the preobese to the obese state.
Thus the primary objective of the following study was to determine
whether plasma GH concentrations differ in OP rats compared with their OR counterparts before dietary changes or onset of obesity. If differences do not exist, subsequent studies could be aimed at elucidating the time point at which dietary or obesity changes affect
GH levels. This would then allow studies to identify factors important
in this metabolic perturbation. If differences in GH do exist before
animals are fed the high-fat diet, further studies to examine the
factors underlying these changes could be pursued.
 |
METHODS |
Animals.
All procedures involving animals were approved by the Animal Care and
Use Committee of Eastern Virginia Medical School. Twenty male
Sprague-Dawley rats weighing between 300 and 350 g (Charles River
Laboratories, Wilmington, MA) were individually housed in hanging
stainless steel cages. Room temperature was controlled (22 ± 2°C), and lighting was on a 12:12-h light-dark cycle. Food and
water were provided ad libitum throughout the experiment. Initially,
rats were maintained on standard laboratory chow (Purina Mills, St.
Louis, MO) and were not switched to the experimental diet until after
blood sampling occurred. Rats were cannulated in the jugular vein and
allowed 1 wk of recovery before sampling. However, cannulas were
aspirated, flushed with heparinized saline (50 IU/ml of heparin; Sigma,
St. Louis, MO), and heplocked with 0.1 ml of heparin (500 IU/ml) daily
to maintain patency.
On the day of sampling, extension cannulas were connected to the
exteriorized jugular catheter to allow remote blood sampling. Blood
samples (100 µl) were drawn in 1-ml heparinized syringes at 20-min
intervals for a period of 200 min. All animals were sampled at the same
time of day, between 0900 and 1300, to reduce influence of diurnal
rhythms on GH secretion. A total of 11 samples was obtained from each
animal. These samples were immediately centrifuged, and the
plasma was stored at
20°C until assay for GH.
One week after the blood samples for GH analysis were obtained, the
rats were fed a purified MHF diet (32.5% of kcal or energy as fat;
D12266, Research Diets, New Brunswick, NJ), described previously (26),
ad libitum. Food intake and body weights were monitored weekly, with
intake corrected for spillage. After divergence of rats into obese and
OR populations, animals were killed by decapitation 15 wk after the MHF
diet was initiated. Trunk blood was collected in
K+-EDTA tubes, and plasma
was stored at
20°C until analysis. Abdominal fat pads
(perirenal, epididymal, and mesenteric) were excised, weighed,
and frozen. Carcass weights were also obtained minus fat pads for
calculation of the index of adiposity.
Assays and calculations.
Plasma GH levels were measured in duplicate by RIA, using the reference
standard rat GH-RP2, and materials were obtained from National Institute of Diabetes and Digestive and Kidney Diseases as
previously described (7). Radiolabeled GH was iodinated with
125I obtained from Amersham Life
Sciences (Arlington Heights, IL). The mean detection limit was 1.3 µg/l, and the mean intra-assay covariance for GH concentrations <20
µg/l was 10.3%. Samples with GH concentrations >20 µg/l were
diluted and reassayed. Episodic GH concentrations were integrated over
the 200-min sampling period, and cluster analysis in a 1 × 1 matrix was conducted to determine discrete parameters of GH pulsatility
(22). Dietary obese and OR populations were determined by subjecting
frequency plot of body weight gain to chi-square analysis as described
previously (26). The seven animals with the lowest body weight gain
were defined as resistant (OR), whereas the seven rats demonstrating the greatest weight gain were labeled OP. The index of adiposity was
calculated as the sum of the fat pad weights (in g) divided by the
carcass weight of the animal minus fat depots (in kg). Other data values, represented as means ± SE, were compared between the two groups by Student's t-test
(42).
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RESULTS |
Food intake, body weight, and composition
data.
Body weights of Sprague-Dawley rats fed the MHF diet are presented in
Fig. 1. Initial body weights of the OP rats
(385.5 ± 17.3 g) did not differ from those of the OR subpopulation
(387 ± 8.4 g), but after 4 wk of the MHF diet, differences in body weight became apparent. At that point, body weights of OP rats were
13% greater than those of the OR group
(P = 0.025). Body weights continued to
diverge over the 15-wk period, and final OP body weights were 35.5%
greater than those of the OR group (P < 0.0001).

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Fig. 1.
Body weights of male Sprague-Dawley rats fed a moderately high-fat
(MHF) diet for 15 wk. Data are means ± SE;
n = 7 for both groups.
Obesity-susceptible rats are labeled as obesity prone (OP), whereas
those resistant to obesity are referred to as obesity resistant (OR).
* Significantly different from OP body weight means at equivalent
week (P < 0.05 or less) by
Student's t-test.
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Food intake data are presented as total cumulative energy intake as
well as relative food consumption (Table
1). OP rats consumed 32% more food over
the course of the 15-wk dietary regimen compared with OR animals
(P = 0.001). However, relative food
consumption, calculated as food consumed per kilogram of body weight,
was not different between groups at week
15. Consumption expressed in this manner also did not
differ for weeks 1-14 (data not
presented). Efficiency of weight gain, calculated as body weight gain
(in g) divided by kilojoules of energy consumed times
103, was 74% greater for OP
(P < 0.0001) compared with OR rats
for the entire study period.
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Table 1.
Food intake, relative food consumption, efficiency of weight gain, and
thyroid hormone concentrations in rats fed a moderately high-fat
diet for 15 wk
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Fat pad weights obtained from OP and OR rats at the end of the study
are presented in Fig. 2. Every fat pad
depot from OP rats weighed significantly more than the respective OR
depot. The greatest difference was observed in the mesenteric depot, which was 2.6-fold heavier in the OP than in the OR animals
(P < 0.0001). Perirenal fat pads
differed by only twofold (P = 0.0014) and were the least-different depot in terms of weight. The epididymal depot and total fat depot weights were similarly 2.2-fold greater in
the OP group (P < 0.0001 for both).
The index of adiposity reflected the increased body fat content of the
OP animals and was 67% higher in the OP compared with the OR
rats (P = 0.0003, Fig.
3).

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Fig. 2.
Total and individual (mesenteric, perirenal, and epididymal) fat pad
weights of male Sprague-Dawley rats fed an MHF diet for 15 wk. Data are
means ± SE; n = 7 for both groups.
* Significantly different from mean of equivalent OP group fat
depot (P < 0.05 or less) by
Student's t-test.
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Fig. 3.
Index of adiposity (g total fat/kg carcass wt fat) calculated
from rats fed an MHF diet for 15 wk. Data are means ± SE;
n = 7 for both groups.
* Significantly different compared with OP group
(P = 0.0003) by Student's
t-test.
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GH secretion data.
Total integrated plasma GH values are presented in Fig.
4 for the 200-min blood-sampling period.
For the equivalent time, GH released was 2.1-fold greater in the OR
rats than in the OP group (P = 0.037).
The GH peak height (Fig. 5) was determined also to be 2.1-fold greater in the OR group
(P = 0.025). There were no differences
in GH peak frequency, peak duration, or mean nadir level between
groups. Representative GH secretion profiles for both OP and OR groups
are shown in Fig. 6.

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Fig. 4.
Total integrated growth hormone (GH) secretion in obesity-susceptible
(gainers) and OR (resisters) Sprague-Dawley rats over a 200-min
sampling period before placement of animals on an MHF diet. Data are
means ± SE; n = 7 for both groups.
* Significantly different compared with gainers
(P = 0.037) by Student's
t-test.
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Fig. 5.
Mean peak GH concentrations in obesity-susceptible and OR
Sprague-Dawley rats during a 200-min blood-sampling period before
placement of animals on an MHF diet. Data are means ± SE;
n = 7 for both groups.
* Significantly different compared with gainers
(P = 0.025) by Student's
t-test.
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Fig. 6.
Plasma GH concentrations over sampling period are presented for an OR
(animal no. 517;
A) and an OP
(animal no. 510;
B) rat. Samples were obtained before
placing rats on MHF diet.
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DISCUSSION |
This study further characterizes the diet-induced obese rat model with
regard to GH deficits. As in previous experiments, Sprague-Dawley rats
fed the MHF diet (26) diverged into OP and OR populations. The data
reported here suggest that these groups differ metabolically even
before MHF challenge, which accounts for their end-point differences in
body weight and fat content. Earlier data (27) have demonstrated lower
GH levels in the obese subpopulation. These data led to the question of
how much of that difference is induced by the dietary fat vs. being due
to a different endocrine or metabolic status before dietary fat
challenge. In other words, does the dietary fat somehow differentially
trigger endocrine responses in the OP rats that are different from
those of OR animals, or does the endocrine status of the preobese rats determine how dietary fat will be utilized? The data obtained in
this study would suggest that the latter situation occurs.
Two responses observed in the OP group may be the result of GH
deficiency rather than the cause of suppressed GH secretion. These are
the increased food efficiency and increased adiposity observed in the
OP rats. Both of these responses have been shown in many species,
including humans, to be regulated by GH concentrations. For example,
porcine somatotropin administration to swine increases feed efficiency
while dramatically decreasing carcass fat deposited compared with
noninjected littermates (43). Porcine somatotropin injections also
increase lean muscle mass in swine, conserving protein while utilizing
fat for energy needs (23). This is also confirmed by the decreased
urinary nitrogen excretion observed in swine administered porcine
somatotropin (23). Thus fat is preferentially used as fuel, whereas
protein is stored to account for increased efficiency. However, in the
case of the OP rats, it would appear that increased food efficiency is
tied to decreased rather than increased GH concentrations. This might
be explained by the nature of the weight gain in the obese rats vs. the
GH-injected swine. In the former case, increased body weight gain
appears to be in the form of fat, especially the abdominal depot (Fig. 2). Regardless of whether the fat is expressed as absolute weight or
relative to body size, the fat depots of the OP rats significantly exceed those of the resistant rats. The index of adiposity data further
confirms the body fat accumulation in obese animals (Fig. 3). This
index has been shown to correlate extremely well with body composition
analysis data in mice (46), although we and others have successfully
utilized this index for other species (28). One possible explanation
for the difference in efficiency of weight gain may be that the adipose
cells of the OP rats more easily take up circulating lipids than those
from resistant rats. Because the MHF diet differs from chow or control
diets in the percentage of fat employed, both prone and resistant rats
would have had exposure to greater-than-normal levels of circulating lipids in this study than with less calorically dense diets. A greater
proportion of these circulating fats was deposited in the depots of the
OP animals compared with those that remained lean. In this experiment,
as calculated, the fat gain appears to be greater than suggested by the
index of adiposity. This may be due, in part, to increased lean body
mass on the part of the OP rats, but body composition was not
determined in this study. Plasma leptin concentrations also did not
differ initially between preobese and preresistant, although they were
different at the termination of the experiments after divergence of
body weight (unpublished data).
Although it is still not established that GH is a causative factor in
the increased fat deposition, differences in GH before the initiation
of the diet strengthen the possibility for direct GH involvement. Our
laboratory and others have demonstrated that plasma insulin levels
often increase along with circulating glucose concentrations over the
course of the dietary treatment (27, 28, 31). However, we observed
neither hyperglycemia nor hyperinsulinemia in OP rats before feeding
the Sprague-Dawley rats the MHF diet. Thus, although it is possible
that hyperinsulinemia leads to greater adiposity, it is more likely
that decreased GH secretion initiates divergent body weight response to
the dietary fat. Moreover, GH decreases the effect of insulin on
glucose oxidation in adipose tissue in vitro (37). In the animal model
characterized here, the GH deficit in preobese rats may lead to an
enhanced response of fat cells to insulin. Because caloric density is
increased along with fat content in the MHF diet, increased insulin
effectiveness along with increased substrates could initiate fat cell
size increases in obesity-susceptible rats.
In addition to the possible enhancement of the effect of insulin, a
hypothesis that needs to be examined more closely is that lack of GH in
the OP rats reduces the lipolytic capacity or response of the adipose
tissue. If the presence of adequate GH concentrations is necessary for
normal levels of lipolysis, a reduction of GH levels may lead to
decreased ability of the OP rats to utilize fat stores compared with
those that remain lean. If this is true, regardless of whether there is
an enhancement of insulin's action, the fat that is stored would be
less likely to be drawn on to meet energy needs in OP compared with OR
rats. GH is a potent stimulator of lipolysis, and it is capable of
mobilizing fat stores for energy instead of glucose (8, 15,
38-41). This makes GH an effective agent for improving body
composition in humans. However, most studies have focused on effects of
administration of GH to the already obese individual rather than
determining its role in the etiology of obesity. The diet-induced obese
rat model provides an opportunity to examine that question in a
prospective manner.
Another effect of GH is to regulate metabolic rate (20, 36). Whereas
increased insulin effectiveness or decreased lipolysis are specific
changes in nutrient utilization, the metabolic effect of GH is a
general one. Decreased GH leads to a reduction in energy expenditure,
which, in turn, would also help increase efficiency of fat
deposition. With the assumption of equal caloric intake in OP and OR
animals per gram of body weight, decreased energy expenditure of the OP
group would provide more energy substrates for storage as fat. It would
be important to examine whether prone and resistant animals differ in
energy expenditure, as measured by indirect calorimetry, before
exposing the animals to the MHF diet.
There are other possible relationships between GH and lipolysis that
have not been explored here. Aside from altering lipid metabolism, GH
also changes the fat cell response to epinephrine, which may in turn
affect adipose cell size and lipolytic sensitivity (2). The effect of
GH on hormone-sensitive lipase has also been well characterized (15),
and the differential regulation of this enzyme in the two groups may
explain, at least in part, the resistance to obesity observed in some
of the Sprague-Dawley rats fed the MHF diet. Other studies have shown a
role for insulin-like growth factor I, a GH-dependent hormone, in body
fat and lipid mobilization (4, 12). However, it is not possible to
determine to what degree each of these factors plays a role in the
diet-induced obese model at this time. Future studies should surely
explore these mechanisms, especially considering these data.
Finally, the reason for the decreased GH secretion in preobese rats is
unknown. Because frequency and duration of GH pulses did not differ
between the two groups, the deficit is likely to involve mechanisms for
GH storage and/or secretion rather than one regulating
pulsatility. Potential mechanisms would include inducers or inhibitors
of GH synthesis and storage, or composition and amount of releasing or
inhibiting factors. GHRH is one peptide that affects both synthesis and
secretion (1, 18, 44, 45). Thus GHRH or a similar factor would be a
good candidate on which to focus. The attenuated GH pulse amplitude in
rats destined to become obese may also suggest higher somatostatinergic
tone. Conversely, there are a number of hypothalamic factors, including
neuropeptide Y and galanin, that alter GH secretion as well as regulate
metabolism and food consumption. Finally, it is possible that a
neuroendocrine abnormality exists that causes the predisposition to
body weight gain and concurrently decreases GH secretion.
Thus lower GH may be just a marker rather than the cause of increased
obesity. If this is the case, GH levels would still be useful as a
marker to help determine the events initiating the diet-induced obesity in response to elevated dietary fat. The model of diet-induced obesity
described here allows for a systematic and prospective analysis of the
discrete neuroendocrinological mechanisms leading to obesity.
 |
ACKNOWLEDGEMENTS |
We acknowledge the assistance of Dr. Paul Kolm for biostatistical
analysis of GH secretion.
 |
FOOTNOTES |
This work was funded by National Institute of Diabetes and Digestive
and Kidney Diseases Grants R01-DK-46832 (to T. J. Lauterio) and
R01-DK-38449 and a Merit Review Award from the Dept. of Veterans Affairs.
Address for reprint requests: T. J. Lauterio, Dept. of Physiology,
Eastern Virginia Medical School, PO Box 1980, Lewis Hall, Norfolk, VA
23501.
Received 16 December 1997; accepted in final form 24 March 1998.
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