The effect of exercise training on leptin levels in obese
males
W. J.
Pasman1,
M. S.
Westerterp-Plantenga2, and
W. H. M.
Saris1
1 Maastricht University,
Department of Human Biology, 6200 MD Maastricht; and
2 Open University, 6401 DL
Heerlen, The Netherlands
 |
ABSTRACT |
The effect of endurance training on plasma
leptin levels was investigated in 15 obese male subjects (age 37.3 ± 5.2 yr, body weight 96.5 ± 13.6 kg, and body mass index 29.8 ± 3.0 kg/m2) in a weight
loss and exercise program. After 4 mo of treatment consisting of a very
low energy diet (VLED) and endurance exercise training (3-4 times
weekly, 1 h sessions, moderate intensity), two groups were formed. One
group continued the exercise sessions (trained subjects,
n = 7) and the other group stopped
with the exercise program (control, n = 8). Measurements of anthropometry, aerobic power, and fasted blood
samples were executed at fixed time points (0, 2, 4, 10, and 16 mo).
With partial regression analysis, keeping the changes in insulin and
body fat percentage constant, it was shown that the number of hours of
exercise training was significantly correlated with changes in leptin
levels, during the 16-mo period
(r = 0.56, P < 0.05). Changes in insulin levels were significantly related to the changes in leptin levels
(r = 0.47, P < 0.05), which were less for
changes in body fat percentage (r = 0.42, P = 0.07). During the VLED, the
change in insulin concentration affected leptin levels significantly
(r = 0.79) but changes in body fat
percentage were not noted. It is concluded that endurance exercise training decreased plasma leptin levels independently of
changes in plasma insulin levels and body fat percentage.
endurance training; insulin; obesity
 |
INTRODUCTION |
THE ISOLATION OF the
ob gene in mice by Friedman et al.
(10) has renewed interest in body weight regulation and the
pathophysiology of human obesity. The
ob gene product leptin is secreted
from adipocytes, and it is postulated that leptin acts as a humoral long-term feedback signal to the central nervous system and in particular to the satiety center in the hypothalamus (3, 27, 32).
Ob/ob mice not producing leptin
responded to high levels of injected leptin with decreased food intake,
a decrease in body weight, an increase in energy metabolism, and
normalization of glucose and insulin concentrations (11,
24). In human studies it was found that obese subjects
have high leptin concentrations, which might indicate that they are
resistant to leptin. Several potential defects have been suggested such
as 1) a defect in the blood-brain
barrier transport, 2) a defect in
the leptin receptor in the brain, or
3) a defect in the coupling with
neuropeptide Y resulting in altered food intake (27).
The relationship between fat mass and leptin, which is also found in
humans (7), might be affected by mechanisms acting on fat mass. The
insulin hormone is thought to be important in this control mechanism
(8, 22). Feeding and starvation (an increase and a decrease of fat
mass, respectively) have been found to affect leptin and insulin levels
(7, 19). It has been suggested that insulin can be viewed as an up- and
downregulator of ob gene expression as
was shown in lean rats (8), whereas only upregulation was present and
functional in obese animals. Circumstantial evidence suggests a role
for the adipocyte in the genesis of insulin resistance. Recent work of
Cohen and colleagues (5) suggested that secretion of leptin by an
enlarged store of adipose tissue may cause insulin resistance, because
of insulin-antagonizing effects of leptin (5, 33).
Not much information is available about the effect of long-term
exercise on the relationship of body fat and leptin. Inasmuch as it is
known that exercise can be of therapeutic value for diabetic patients,
because of an increase in insulin sensitivity (4), the question arises
concerning what the effect of exercise might be on the leptin-insulin
interaction. Is an exercise intervention effective in
relation to obesity by means of an adaptation of leptin levels related
to changes in body fat?
In this study the effect of an exercise intervention after a weight
loss treatment is studied in relation to long-term weight maintenance
in obese male subjects. Changes in body weight, body fat percentage,
insulin, and leptin concentrations were examined in relation to
training status of the subjects. It is hypothesized that long-term
endurance training might reduce leptin levels in relation to body fat,
possibly mediated by insulin.
 |
METHODS |
Subjects.
In this study, 15 sedentary obese males participated [age 37.3 ± 5.2 yr, body mass index (BMI) 29.8 ± 3.0 kg/m2, and body wt 96.5 ± 13.6 kg]. Physical characteristics of the subjects before the study
are given in Table 1. Subjects were medically examined by a physician
before they entered the study. The experimental procedures and
potential risks of the study were explained both verbally and in
writing. A written informed consent was obtained from each subject at
the start of the study. The study was approved by the Ethics Committee
of the Maastricht University.
Study design and protocol.
All subjects started a very low energy diet (VLED), a protein-enriched
formula diet providing 2 MJ daily (44% energy protein, 14% energy
fat, 42% energy carbohydrate), for 2 mo in addition to a training
program of 4 mo. The exercise performed consisted of low- to
moderate-intensity exercise bouts of 1 h, three to four times a week.
After the VLED, the training sessions were continued for another 2 mo
to prevent a fast regain of the weight lost. After these 4 mo two
groups were formed; one group continued the training sessions
(n = 7) and the other group stopped
training (n = 8). The latter group
served as the controls and performed sports activities less than once a
week as before the intervention. Physical characteristics (the same as
presented in Table 1) were not significantly different between the
trained and the control groups at 4 mo.
The group that continued training trained with a local triathlon club,
where they could train under supervision at a moderate to severe
intensity all three events of the triathlon (swimming, cycling, and
running). They could also train by themselves, thereby not restricting
them to certain training hours (because of shift-work some subjects
were otherwise not able to train).
Compliance.
Compliance to training sessions was checked in multiple ways. A
training diary was used for day-to-day activities and remarks (illness,
injury, weather conditions, and so forth). Questionnaires at the time
of measurement to check frequency of training (number of training hours
per week) and visitations of the investigator to training sessions were
also performed to investigate compliance. Compliance to the prescribed
training sessions was 89 ± 26% for the trained group during the
intervention period.
Measurements.
After an overnight fast subjects came to the laboratory at 0, 2, 4, 10, and 16 mo after starting the study at 8 AM for different measurements.
Anthropometry.
Subjects were weighed on a digital balance accurate to 0.1 kg (Sauter
D-7470, Ebingen, Germany). Height was obtained to the nearest 0.1 cm
using a wall-mounted stadiometer (Seca, model 220, Hamburg, Germany).
The BMI was calculated by body weight × height
2
(kg/m2). The distribution of fat
was investigated by measuring the waist and hip circumferences and
calculating the waist-to-hip ratio (WHR) and sagittal diameter
(Dsag).
The waist circumference was measured at the smallest circumference
between the rib cage and the iliac crest, with the subject in the
standing position. The hip circumference was performed at the level of
the widest circumference between the waist and the thighs. The WHR was
calculated by dividing the waist circumference by the hip
circumference. For determination of the
Dsag, the
distance between the abdomen and the back, a stadiometer was used with
the subject in the supine position.
The deuterium dilution technique was used for measurement of body
composition in this study (29).
2H20
dilution was used to measure total body water (TBW). Subjects were
asked to collect a urine sample in the evening just before drinking the
deuterium-enriched water solution. After consumption of this solution
no further consumption was allowed. Ten hours after drinking the water
solution another urine sample was collected. The dilution of the
deuterium isotope is a measure for TBW of the subject (20). Deuterium
was measured in the urine samples with an isotope ratio mass
spectrometer (VG-Isogas Aqua Sira). TBW was obtained by dividing the
measured deuterium dilution space by 1.04 (29). Fat-free mass was
calculated by dividing the TBW by the hydration factor 0.73.
Blood analysis.
On all test days fasted blood samples were obtained (10 ml EDTA-blood
and 10 ml serum) from the subjects before 9 AM. Subjects were
instructed not to perform strenuous exercise the day before the test
day and train at least 12 h before blood sampling. The time period
between the last exercise bout and blood sampling was always at least
12 h. The plasma blood samples were mixed with EDTA to
prevent clotting and were centrifuged immediately. Serum blood was
centrifuged after 1 h at room temperature. Blood samples were stored at
80°C until further analysis. Plasma insulin was measured
using a double antibody radioimmunoassay (RIA) for human insulin (Kabi
Pharmacia Diagnostics, Uppsala, Sweden). Leptin analysis was performed
with an RIA (Linco Research, St. Charles, MO), based on a study of
Maffei and colleagues (19). The within-assay analytic coefficient of
variation of the RIA kit ranged from 3.4 to 8.5%, and the interassay
coefficient of variation ranged from 3.6 to 6.2%. The within-subject
of variation for repeated sampling was 2.9 ± 2.4%,
whereas the between-subject coefficient of variation was 65.6%. The
values measured were in the range of detection (range 0.5-100
ng/ml). All determinations of leptin levels were run in a single assay
to eliminate interassay variation. Insulin and leptin were both
determined in duplicate.
Maximal performance test.
To investigate the effect of the training program on performance
capacity [maximal oxygen uptake
(
O2 max) and maximal
power output (Wmax)], an
incremental exercise test was performed on an electromagnetically
braked cycle ergometer (Lode, Groningen, The Netherlands). After a
warm-up period of 9 min (5 min at 40 W and 4 min at 80 W) the workload
was increased every minute with 20 W until exhaustion. The
Wmax was calculated using the
total time cycled at the exercise test. The highest workload completed for 1 min (Wcompleted) and the
number of seconds (X) that the final
increase of 20 W was maintained were added according to the formula:
Wmax = Wcompleted + [(X/60) × 20].
Criteria for maximal performance were forced ventilation, leveling off
of oxygen uptake, or a respiratory exchange ratio above 1.1. The oxygen
uptake during the test was measured continuously using a computerized
open system (Oxycon Beta, Mijnhardt, Bunnik, The Netherlands).
Data analysis.
In the text, table and figure data are presented as means ± SD. In
the present study the effect of 12 mo of endurance training on leptin
concentration in weight-reduced males was examined. The data measured
at 10 and 16 mo were therefore averaged, and the change in parameter
(
) was compared with the change in parameter during the 4-mo
treatment. Regain of the parameter during the intervention period
(4-16 mo) is expressed as a percentage of the treatment period
(0-4 mo). However, factors known to be related to leptin, such as
insulin concentration and body fat percentage, could disturb the
relationship between exercise and leptin. This relationship should
therefore be studied by means of partial regression analysis, to
correct for changes in insulin concentration and body fat percentage.
The amount of variance explained by the factors leptin, insulin, and
body fat percentage then can be evaluated with multiple regression
analysis.
Statistical analysis.
Differences between the group that trained continuously and the group
that had stopped training after 4 mo were tested
nonparametrically with the Mann-Whitney test. Partial correlation
coefficients (pcc) were calculated by use of residual sum of squares of
multiple (RSS2) and simple regression analysis (RSS1), that is,
. Multiple
regression analysis was used to calculate the amount of explained
variance of the variables. For all statistics performed statistical
significance was set at P < 0.05.
 |
RESULTS |
Physical characteristics of the 15 male participants are presented in
Table 1. No significant differences were
found in baseline characteristics between the trained and the control
group. At 4 mo, physical characteristics appeared to be similar too
(data partly shown in Table 2).
Training intervention.
The effectiveness of the training intervention studied is examined by
comparison of the training status of the two groups. In Table
3 the
O2 max and
Wmax measured at the maximal
performance test are presented for the two groups, expressed per
kilogram body weight.
The training status parameters
O2 max and
Wmax were equal at the beginning
of the study and at 2 and 4 mo. The group that continued the training
sessions showed significantly higher power output levels and
O2 max at 10 and 16 mo. On the basis of these differences found in training status
we can compare these groups and study the effect of differences
in training status.
Anthropometry and blood parameters.
In Table 2 the parameters body weight, BMI, body fat percentage, WHR,
and Dsag are
shown for the entire period for the trained and control
groups. Body fat percentage determined with the deuterium dilution technique was significantly lower for the trained compared with the control group at 16 mo (at 10 mo,
P = 0.06). Significant differences
were also found between the groups with respect to WHR at 16 mo. The
leptin concentration decreased for both groups during the VLED
(0-2 mo) from 10.7 ± 5.1 to 3.1 ± 1.3 ng/ml for all
subjects (no differences between the two groups). During the intervention period, leptin concentration changed significantly and was
different between the two groups at 10 and 16 mo. For the insulin
concentrations no differences were found between the groups over
the entire period.
Regain of waist, WHR, and
Dsag during the
intervention period (
4-16 mo) was significantly less for the
trained compared with the control group
(Fig.1). Signifi-cantly less regain
of waist, WHR, and
Dsag was found
for the trained compared with the control group.

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Fig. 1.
Regain of anthropometric parameters at 16 mo (increase is expressed as
percentage of amount lost during 4 mo of treatment). Increase in waist
( waist), waist-to-hip ratio ( WHR), and sagittal diameter
( Dsag) are
presented for trained (hatched bars) and control groups (filled bars).
* Statistical significance was set at
P < 0.05.
|
|
Relationship of insulin, body fat percentage, and exercise with
leptin.
The relationship between body fat percentage and leptin was studied by
relating the change in body fat percentage during the 2-mo VLED with
the change in leptin concentration over the same period. Partial
regression analysis revealed that the change in body fat percentage was
not correlated with the changes in leptin (pcc = 0.27, not
significant). However, the change in insulin was correlated with the
changes in leptin concentration (pcc = 0.79, P < 0.01). The change in body fat
percentage during the intervention period (
4-16 mo) was,
however, significantly correlated with the change in leptin
concentration during this same period (r = 0.68, P < 0.05)
(Fig.2).

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Fig. 2.
Relationship between change in body fat percentage during intervention
(4-16 mo) and change in leptin concentration (open squares).
Regression line and correlation are presented.
|
|
With simple regression analysis a relationship was found between
O2 max (kg body wt) and
leptin levels with training (on average over the four time points
r =
0.57 ± 0.1, P < 0.05). Before the training
intervention no such relationship was found (r =
0.08,
P = 0.79). The effect of training on
plasma leptin levels was further analyzed using partial regression
analyses (Table 4).
Changes in insulin, body fat percentage, and number of training hours
per week of all subjects were analyzed in relation to leptin levels
measured, when corrected for possible interactions. As found for
changes during the VLED, changes in leptin levels over the entire
period were related to changes in insulin (pcc = 0.47, P < 0.05). During this
time period, a trend for changes in body fat percentage affecting
leptin changes was also found (pcc = 0.42, P = 0.07). Analysis of the influence
of training hours when the change in body fat percentage and the change
in insulin were kept constant showed a pcc of 0.56 (P < 0.05), indicating that training
was an independent factor correlated with changes in leptin levels.
Multiple regression analysis of two variables (
insulin and
body
fat percentage) explained 44% of the variance of leptin. Inclusion of
the amount of training hours resulted in a significant increase in
explained variation to 61%.
 |
DISCUSSION |
Exercise.
The main result of this study is the independent effect of training on
leptin concentration. So far no studies are known in humans in which an
effect of exercise training on leptin concentration is reported
independent of body fat and insulin levels. Because the trained group
had significantly lowered leptin levels after 1 yr of exercise
training, we analyzed the independent effect of training on leptin
levels when corrected for the changes in insulin and body fat
percentage during the long-term exercise intervention. The number of
training hours a week correlated significantly with the changes found
in leptin levels. Recently it was found that sex steroid hormones too
were independent of body fat related to leptin levels (9).
Because it is known that some obese subjects overestimate their
physical activity (16), the training sessions were continuously visited
by the investigator (W. J. Pasman) and training diaries were frequently
examined to be certain that reliable training data were obtained. The
relationship found between training hours and leptin may suggest that
exercise effectively resulted in reduced leptin secretion or an
elevated elimination of leptin. This effect was not found at 10 mo of
the study, indicating that the duration of training and the difference
in training status between the two groups might be important. Our
findings could not be explained by the pulsatile leptin secretion
recently reported by Licinio and co-workers (17), because we sampled
blood at the same standardized moments of the day. Our findings are
supported by the results of Hickey and co-workers (12), who reported
that male trained distance runners also had reduced leptin levels. In
another study Hickey et al. (13) found a reduction in serum leptin
levels in female subjects after a 12-wk training intervention, which was not found in the participating males. This might indicate that the
duration of the training intervention is important especially for
males. The 17.5% reduction in serum leptin level found by Hickey et
al. (13) was less than the reduction of 23% in our study. A study of Kohrt and colleagues (14) in elderly
women (aged 60-72 yr) further indicates that women show lowered
leptin levels in response to exercise. The 23% reduction in leptin
levels found in that training group was similar to the level found in the male population in the present study. Low levels of leptin were
also found in highly trained women vs. controls by Ryan and Elahi (28).
All results support the suggestion that training lowers leptin levels.
Hickey and co-workers (13) suggest that the gender-specific response to
training is based on the difference in insulin-resistance between males
and females; males being the most insulin-resistant might need more
time and a greater stimulus to respond with lowered leptin levels.
According to Kohrt et al. the reduction in leptin concentration is an
indirect consequence of exercise; the reduction in fat mass, caused by
training, seemed to be the main factor related to leptin (14). This is
in contrast to the findings in the present study. After correction of
the relationship of leptin with body fat percentage and insulin, we found a clear relationship in regard to the amount of training performed a week. Perhaps the clear difference in exercise protocol in
the studies (intensity and duration per training session in the present
study were higher and longer) and the participating subjects (male,
middle-aged subjects vs. elderly females in the study by Kohrt et al.)
can explain the differences found in relation to training and leptin.
The recently published results of Pérusse and co-workers (25) and
Ostlund and co-workers (23) also stress the relationship between leptin
and exercise via the changes in body fat. The much longer training
period in the present study (16 vs. 4-5 mo) might explain the
independent effect of training found in the present study,
whereas Pérusse and co-workers found that after correction for
fat mass no effect of exercise was seen. As mentioned previously at 10 mo, no independent effect of training was found and therefore duration
might be an important factor. The difference in BMI of the male
subjects at the start of the study (25.5 ± 5.0 kg/m2) in comparison with the
subjects participating in the present study (29.8 ± 3.0 kg/m2) (25) might further stress
that exercise in obese subjects normalizes leptin levels, resulting in
more pronounced effects in obese subjects. In the study by Ostlund et
al., 106 subjects between 60 and 70 yr old were included and thus
only a low range of the
O2 max was
examined.
Data for trained rats showed that endurance training significantly
decreased the ob gene expression (10,
36). Insulin sensitivity and fat cell size were postulated to be
important regulators of ob protein
mRNA expression (36). The regulation is complex because exercise
training not only influences obesity but also insulin resistance as
well as body composition (2, 6). These three parameters are mutually
related. All findings together suggest that exercise and leptin levels
are causally related, although a spurious relationship or confounding
factors such as a negative energy balance that could disturb the
relationship cannot be ruled out. Our data support the existing
relationship but do not inform us about cause and effect.
There may be another possibility that could explain the differences in
leptin found in the trained and control group after 16 mo of exercise
training. It has already been found that leptin is bound by plasma
proteins (31). A change in ratio of leptin free or bound at plasma
proteins might result in more or less active leptin action. The total
amount of leptin could be stable but the ratio of bound and free
leptin, and thereby the activity of leptin, might be changed by
exercise training. Differences in the ratio of free and bound free
fatty acids for example have already been found for trained vs.
untrained subjects by Turcotte and co-workers (34).
Insulin and body fat percentage during VLED and long-term
intervention.
In the present study we found that 2 mo of energy restriction resulted
in significantly lowered leptin levels in both groups as was found by
others (7, 19). Partial regression analysis showed that changes in
insulin levels during the energy-restricted period were significantly
correlated with changes in leptin levels and that changes in body fat
percentage were not related to changes in leptin levels. Also, a simple
regression analysis between body fat percentage and leptin (directly
after VLED at month 2) showed that
these parameters were not related, which could be explained by the
negative energy balance (extreme negative energy balance because of the
VLED). This dissociation of serum leptin concentration and body fat
content was recently also shown by Scholz and co-workers (30). They
concluded that long-term hypocaloric diet uncouples the relationship of
leptin and changes in body fat (30). The low levels of leptin as we
found after the diet intervention and still at 4 mo may precede weight
gain, as was recently suggested by Ravussin and co-workers (26). A
lower production of leptin by the adipose tissue may play a role in the
pathophysiology of obesity but could also indicate that the sensitivity
of the tissue to leptin has increased and that leptin concentration has
therefore been adapted. Further studies are needed to find out whether
lowered leptin levels in blood are useful markers for the development of obesity.
In the present study at 4 mo the subjects were weight stable, and no
negative energy balance seemed to be present. Therefore, the
differentiation between the groups from that time point on could be
related only to exercise level and not to energy restriction. Partial
regression analysis revealed that
insulin affected
leptin during
VLED, indicating that insulin and leptin are related also when
corrected for body fat percentage. The change in insulin significantly
affected leptin levels, but in the long term the change in body fat
percentage influenced leptin levels. The change in body fat percentage
over 1 yr of training and the change in leptin during the intervention
period were related (Fig.2). Together with the lowered leptin levels
for the trained group, it is concluded that the regulation of insulin
and leptin are interrelated, although the mechanism and direction
behind this remain to be elucidated. Recently it was hypothesized that
insulin would act as an up- and downregulator of leptin in lean rats,
whereas in obese rats only upregulation works (8). Zheng and co-workers
(38) reported that ob mRNA is
upregulated by insulin infusion in abdominal adipose tissue of a fasted
rat. Insulin would be directly involved with the expression of
ob mRNA at a transcriptional level as
was found in cultured mature fat cells (15). Our data support the
hypothesis that insulin might have a regulatory role in obese males,
because, after correction of body fat percentage, clear relationships
of insulin still exist with leptin. However, the direction of
regulation, insulin-regulating leptin or leptin-regulating insulin, is
still unclear, although Cohen and co-workers (5) and Taylor et al. (33)
recently suggested that in vitro insulin is modulated by leptin. This
interaction of insulin and leptin warrants further study.
Body fat percentage or body fat distribution?
In the present study a relationship between body fat percentage and
body fat mass with leptin was found (on average
r = 0.76, P < 0.05 for body fat percentage at
all time points measured; with fat mass on average
r = 0.83, P < 0.05; data not shown). This
strong relationship has already been found by others (7, 18). The
difference in body fat percentage between the trained and control group
at 16 mo might be a consequence of the training sessions performed as
has been shown before (35). The body composition differences are
important because no significant differences in body weight and BMI
were found at 16 mo. Therefore, the differences in body composition
between the two groups could be important with respect to differences
in leptin levels found.
However, fat distribution measured by WHR or
Dsag differed
significantly between the two groups at the end of the study. In the
present study we found significant differences during the intervention
period in waist circumferences,
Dsag, and WHR
between the two groups. The increased values for the control group
might indicate that the extra regain of fat mass in the control group is probably located in the waist region. Simple regression analysis also revealed significant correlations between the change in waist,
WHR, and
Dsag with the
change in leptin during the exercise intervention period
(r = 0.58, P < 0.05;
r = 0.69, P < 0.05;
r = 0.59, P < 0.05, respectively). These
results are in accordance with the findings of Buemann and Tremblay
(2), who reported that exercise training is negatively correlated with
WHR. Mauriège and colleagues (21) also supported the hypothesis
that the abdominal fat depot is decreased by training. Buemann and
Tremblay further reported that upper body obese patients responded to
exercise with increased insulin sensitivity. Exercise can thus increase insulin sensitivity by lowering percentage of body fat and fat accumulation in the waist region and result in decreased leptin levels
perhaps via a regulation with insulin, which would be in favor of a
role of the fat distribution. Regional differences in
catecholamine-induced lipolysis (1) and site-specific differences in
ob gene expression reported in rats
(38), support the hypothesis that leptin production might be site
specific. This is further supported by the results of Ryan and Elahi
(28), who found that WHR but not other measures for abdominal obesity
(trunk fat by dual X-ray absorption, abdominal subcutaneous fat, and
Dsag) were as
in the present study significantly related to
leptin. However, Ostlund and co-workers (23) recently
showed that there was no independent effect of fat distribution at
leptin levels measured. Correction for body fat percentage resulted in
a disappearance of the negative correlation found between WHR and
leptin (23). In that study the majority of subjects were females (120 females vs. 84 males), which is in contrast to the homogeneous group of male subjects in the present study. The abdominal fat distribution found in males might be less obvious in a mixed population in contrast
to our group of subjects. Furthermore, the differences in age range (in
the present study 28-46 yr vs. 18-80 yr in the study of
Ostlund et al.) might explain the differences found with fat
distribution and leptin.
On the basis of the findings in the literature and our own data we
conclude that the localization of the main fat depot might have
consequences for the regulation of leptin metabolism. It is concluded
that exercise training decreased plasma leptin levels independently of
changes in plasma insulin levels and body fat percentage. In addition
to training, the changes in body fat percentage and moreover changes in
insulin seem to be affecting the regulation of leptin levels.
 |
ACKNOWLEDGEMENTS |
The authors thank Dr. A. Kester for statistical advice.
 |
FOOTNOTES |
Address for reprint requests: W. J. Pasman, Maastricht Univ., Dept. of
Human Biology, P. O. Box 616, 6200 MD Maastricht, The Netherlands.
Received 18 March 1997; accepted in final form 9 October 1997.
 |
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