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1 Maastricht University, 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
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.
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.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
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.
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.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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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).
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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.
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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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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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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).
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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%.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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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 theO2 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 thatinsulin 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.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. A. Kester for statistical advice.
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FOOTNOTES |
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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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Top
Abstract
Introduction
Methods
Results
Discussion
References
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