Gender dimorphism of body mass perception and regulation in mice
1 German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal,
Germany
2 Franz-Volhard Clinical Research Center Berlin, Medical Faculty of the
Charité, Humboldt-University, Berlin, Germany
* Author for correspondence (e-mail: Klaus{at}mail.dife.de)
Accepted 1 June 2004
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Summary |
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Key words: body mass set-point, energy expenditure, body composition, ponderostat, obesity, gravity, sex difference, mice
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Introduction |
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Most mammals show gender dimorphisms in body mass and composition, and
there is ample evidence that energy homeostasis and substrate utilization are
regulated differently in males and females
(Cortright and Koves, 2000).
Very recently it was shown that male and female rats display differential
sensitivity to central insulin and leptin levels with regard to food intake
regulation (Clegg et al.,
2003
). However, even extensive discussions of body mass regulation
do not address the possibility of gender differences in the basal regulatory
mechanisms (Jequier and Tappy,
1999
).
We therefore tested the hypothesis that body mass per se is perceived and regulated, and that there might be gender differences in this regulation. In order to increase body mass artificially, we implanted inert weights corresponding to 10% of initial body mass into the abdominal cavity of mice. If mice are able to detect the increase in total body mass (MTB) and there exists an individual set point of body mass we would expect them to show a compensatory decrease in biological body mass (MBB, body mass exclusive of the weight load) to restore the set-point MTB. To control for surgical stress and the volume effect of the implant, we included a sham operated group (SO) and a group with an implant of the same volume, but lower mass, corresponding to only 23% of body mass (LO), in addition to the 10% implant group (HI).
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Materials and methods |
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Implantation of weight loads
Animals were divided randomly into three treatment groups: a sham-operated
group (SO), a group that received light weight loads (LO) and a group that
received heavy weight loads (HI). LO and HI weight loads corresponded to
23% and 10% of initial body mass, respectively. Implants were composed
of a rod-shaped core (1.4 cm length, 0.8 cm diameter) and a wax coating (Elvax
Wax, Minimitter Co., Sunriver, OR, USA). The core of LO weight loads consisted
of plastic tubing filled with cotton. HI weight load cores consisted of a
metallic cylinder. For implantation of the weight loads, mice were
anaesthetized with ketamin (1 µl g1; Ketamin Gräub,
A. Albrecht, Aulendorf, Germany) and xylazinhydrochlorid (0.1 µl
g1; Rompun: BayerVital, Leverkusen, Germany). Weight loads
(see below) were disinfected and implanted into the abdominal cavity. The
abdominal cavity was sutured using absorbable surgery thread (PGA Resorba,
Resorba, Nürnberg, Germany), and skin was closed with clips (Becton
Dickinson, Sparks, MD, USA) that were removed 1 week after the operation. SO
animals were treated exactly like the implantation groups except that no
weight was introduced. Weights were removed 14 weeks after implantation.
Measurements
Body mass and energy intake were measured 3 times per week throughout the
experiment by weighing (BP 2100, Sartorius AG, Göttingen, Germany;
detection limit 0.01 g). We define total body mass (MTB)
as the measured mass of the animals, i.e. including the implant, and
biological body mass (MBB) as the measured mass minus the
implanted weight load.
Energy expenditure was measured by indirect calorimetry of mice housed in
metabolic cages, receiving food and water ad libitum. Measurements
were performed 2 weeks before implantation (background measurement) as well as
2 and 12 weeks after implantation. During indirect calorimetry, urine was
collected daily for determination of nitrogen excretion using a Kjeldahl
method (Proll et al., 1998).
Gas analysis was performed using the analyzing system Advanced Optima
(Hartmann & Braun GmbH & Co. KG, Frankfurt/Main, Germany) containing
an oxygen (Magnos 16) and a carbon dioxide (Uras 14) analyzer. Mice were
measured for two consecutive days. Mice from six cages were measured in
parallel and every 6 min. Energy expenditure was calculated using the
following equation (Frenz,
1999
):
![]() | (1) |
Resting energy expenditure (ERE) was defined as the
mean of the 10 lowest daily values for energy expenditure
(Klaus et al., 1998).
Respiratory quotient (RQ;
CO2/
O2)
and physical activity level (PAL;
ETE/ERE) were calculated.
Body composition was measured at the time of surgery, prior to implantation, and when the weight load was removed after 14 weeks, using dual-energy X-ray absorptiometry (Lunar Piximus, Janesville, WI, USA) in anesthetized animals.
Calculations and statistical analysis
Most of the data are expressed relative to basal values measured 3 weeks
(energy intake), 2 weeks (total energy expenditure, resting metabolic rate)
and 1 week (body mass) prior to implantation, or at implantation of the weight
load (fat mass, lean body mass), corresponding to 100%. Data are shown as
means ± S.E.M. To achieve normal distribution, data for body
mass values at 1 week after weight load and for energy intake were
log-transformed. Baseline characteristics were compared using pooled or
separate variances t-test for equality of means where applicable.
Homogeneity of variances was tested by Levene's Test for equality of
Variances.
Single measurement data were analyzed using analysis of variance (ANOVA), and Dunnett's-test was used as a post-hoc test for multiple comparisons against SO group. Development of body mass, energy intake, and energy expenditure were analyzed using repeated-measures ANOVA. Gender, mass implantation group and an interaction term between group and gender were included in the ANOVA models. To exclude any effects of post-surgical stress in these analyses, body mass and energy intake starting 2 weeks after surgery were included. Significant differences within the sexes were tested using one-way ANOVA including mass implantation group as independent factor. Significance was assumed at P<0.05. Analysis was performed using SPSS 8.0 (SPSS Inc., 1998, Chicago, IL, USA).
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Results |
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Body mass development
Fig. 1 shows development of
MTB, MBB and energy intake throughout
the experiment. Acutely after surgery, all groups showed a reduction in
MTB and MBB
(Fig. 1A,B). Body mass
reduction after 1 week of weight load was more pronounced in HI mice than SO
mice (MTB, P<0.001; MBB,
P<0.001). MTB of male HI mice was 99.6+1.1%,
and was the same as MTB of SO males (P=0.109),
whereas MTB of female HI mice was 102.7+0.8% of the
initial value and significantly higher than in SO females
(P<0.001). Male mice thus showed complete initial compensation of
MTB, in contrast to female mice, and this effect was still
apparent 2 weeks after weight load (see
Fig. 1A).
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Further change in MTB was influenced by gender (P<0.001) and by the mass of the implant (P=0.016). HI mice of both genders showed significantly increased MTB throughout the study period compared to SO mice (Fig. 1A).
Changes in MBB were significantly affected by group (P=0.004) and sex (P<0.001). Up to week 4, MBB was significantly reduced in HI males compared to SO, whereas from week 5 on, changes in MBB were similar in all male mice. However, the MBB of HI males was permanently slightly reduced, by about 35% compared to SO and LO mice. In females, MBB was similar in all groups from week 2 on. Interestingly, from 8 weeks on, female LO mice showed the highest MBB (Fig. 1B) resulting in MTB levels comparable to those of HI females (Fig. 1A).
The gender differences are more obvious in Fig. 2, which shows the time needed to regain initial body mass. Females recovered initial body mass earlier than males (P=0.003). Male HI mice took longer to recover body mass compared to SO males (P=0.011). In females the weight of the implant had no effect on the time required for body mass recovery.
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Food intake
During the first week, energy intake was significantly decreased in both
genders (Fig. 1C). There were
significant effects of group (P=0.026) and sex (P<0.001)
on reduction of energy intake after 1 week. Males decreased their food intake
to lower levels than females. Energy intake of male mice after 1 week was
80.1±3.2% in SO, 61.5±1.7% in LO, and 54.5±3.1% in HI
relative to basal values. Energy intake of female mice after 1 week was
77.8±2.8% in SO, 67.4±3.8% in LO, and 66.1±3.6% in HI
relative to basal values. From the second week on, energy intake of males and
females was similar among the implantation groups. Increased energy intake
following weight load was more pronounced in females of all groups than in
males (P=0.042), presumably because of slightly higher values in HI
females. However, comparison of the different female groups did not reveal
significant differences; P-values for a given time point were between
0.1 and 0.2 for comparison between HI and SO (Dunnett's-test).
When cumulative energy intake from weeks 1 to 14 was calculated, no significant effect of gender could be detected (Fig. 3). The mean cumulative energy intake of LO and HI males seemed to be lower compared to SO males but was only significant for LO males (P<0.05), probably due to lower variation of values in the LO group. Although HI females displayed higher cumulative energy intake compared to SO and LO females there are no significant differences between female groups.
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Body composition
Fig. 4 shows changes in body
composition 14 weeks after weight load in relation to initial values. Increase
in fat mass at 14 weeks after weight implantation was lower in males than in
females (Fig. 4;
P=0.046). SO and LO males increased their fat mass compared to
initial fat mass whereas HI males maintained their initial fat mass, the
differences reaching borderline significance (P=0.052). In contrast,
females increased fat mass in all treatment groups and there were no
differences between the groups (P=0.456). Lean body mass was not
affected by gender or the implanted weight and did not change compared to
initial values (Fig. 4B).
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Energy expenditure
ETE was mainly determined by ERE
(data not shown). ERE was influenced by gender but not by
the implanted weight load (Table
3). Absolute ERE was lower in females than in
males (P=0.006). Following weight load females increased
ERE to a higher extent than males relative to initial
levels (P=0.001). Due to the high variability in
ERE, no significant effect of the implanted weight could
be detected in male and female mice. Physical activity level (PAL) was
significantly affected by sex (P=0.041) with higher values in females
that were consistent with baseline measurements
(Table 1), but it was not
influenced by the implanted weight (Table
3). Respiratory quotient (RQ), i.e. substrate oxidation, was not
affected by weight load or by gender (data not shown).
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Discussion |
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Both genders showed an acute reduction in food intake accompanied by a reduction in body mass, which was obviously due to post-surgical stress. Male mice carrying the heavy implant decreased MBB during weeks 1 and 2 following weight load to an extent that MTB corresponded to basal values. This observation seems to comply with the set-point theory of body mass and a mass-dependent regulation of body mass. However, this effect was only transiently present as MTB increased thereafter and became significantly higher compared to SO males. In addition, the transiently observed recovery of the basal body mass was not present in HI females, which acutely lost less MBB and regained it rapidly to levels similar to SO and LO females. HI males displayed a permanently lower MBB following weight load compared to SO males, the difference accounting for about half of the implanted mass (5%). Although not significant, the permanence of the reduction seems to suggest a real effect. Therefore, in the long-term there might be only a partial compensation of the increased body mass and only in male and not female mice.
The partial compensation observed in males occurred mainly at the expense of fat mass; lean body mass was not changed. This seems reasonable considering that a certain muscle mass is necessary to move an acutely heavier body mass. In addition, since fat contains much more energy per mass unit compared to lean mass, fat loss due to negative energy balance would lead to a lower overall body mass reduction than a loss in lean mass.
Energy intake was not affected by the additional weight in the long-term.
After the initial reduction, male mice of all groups returned to their initial
levels of food intake by the second week after implantation. One could suggest
that the lack of an increase in energy intake in HI males that compensated for
the acute weight loss led to the slightly decreased MBB
compared to SO males. However, HI females also showed normal energy intake but
displayed comparable MBB to SO and LO females. This
suggests that males are either more sensitive in their perception of an
increased body mass or that they showed a higher stress response to the
additional weight compared to females. There are some studies to support the
first suggestion. Firstly, our observations in male HI mice confirm the
results of Adams et al. (2001),
who described a compensatory decrease in MBB following
intraperitoneal implantation of 13 g weights into male deer mice
Peromyscus maniculatus. This reduction was paralleled by a reduction
in food intake, which was significant only for the heaviest implant group (3
g). The authors suggested the existence of a `mechanical set point', referring
to the loading of the musculoskeletal system that leads via unknown
mechanisms to perception of the animal's body mass. However, they did not show
a time course of body mass change or energy intake and investigated male mice
only for a period of 5 weeks. The overall reduction in food intake they
described could thus have resulted from the initial, stress induced reduction
after surgery rather than being the result of a regulated process to approach
the set-point mass. In addition, the authors described that the reduction of
MBB in the 3 g implanted group corresponded to about 1.5
g. This represents a MBB reduction of half the implanted
mass, similar to our study. Therefore, the conclusions drawn from our study
could also be applied to the study by Adams et al.
(2001
).
Secondly, several studies have examined the effect of hypergravity induced
by centrifugation, thereby multiplying the mass load on the body. Overall they
show that hypergravity leads to an acute decrease in body mass in rodents,
associated with acutely decreased energy intake and increased maintenance feed
requirements (Wade et al.,
1997,
2002
;
Warren et al., 1997
). The
decrease in body mass resembles that of male HI mice in our study. In fact,
most of these studies were done in male rodents only. One study that included
male and female rats showed that female rats raised in hypergravity (2.5
g) showed a much less pronounced body mass reduction than male
rats (Wubbels and de Jong,
2000
), suggesting a stricter maintenance of
MBB in females similar to our results.
Thirdly, after i.p. implantation of a telemeter with a weight corresponding
to about 12% of initial body mass into male Swiss Webster mice,
MBB was acutely reduced by the mass of the implant but was
increasing above basal levels by the end of a 14 day period
(Perry et al., 2000). However,
a control group was not included in this study.
It seems that at least in male rats and mice an acutely increased body mass is partially compensated by a reduction in MBB, although to a lower extent than would be expected from the mass of the implant if the maintenance of a mass-specific set-point is assumed. This suggests that a mass-specific set-point regulation of body mass is not accurate or might be impaired by still unknown competing mechanisms. The fact that males in general needed longer to recover their initial MBB than females could point to a higher stress susceptibility of male mice.
We expected an increase in energy expenditure in HI mice, considering the
increased energy demand needed for carrying the additional weight. However,
ERE was only slightly and not significantly increased in
HI animals 2 weeks after weight implantation. The failure to detect
significant group differences in energy expenditure is probably due to the
small sample size, but also to the high intra-individual variability of energy
expenditure. It should be emphasized that only very small effects on energy
expenditure could be expected, since the maximum weight load was only 10% of
body mass, i.e. around 23 g. This is not much considering that mice
normally display daily mass fluctuations in the range of 12 g according
to our own measurements (not shown). Interestingly, physical activity was
apparently also not affected by implantation, as evident from the PAL values.
However, in mice implanted with a telemetry transmitter, their willingness to
practice in running wheels decreased after i.p. implantation
(Perry et al., 2000),
suggesting a decrease in physical activity. In contrast, subcutaneous
implantation in rats of telemetry transmitters corresponding to 15% of the
animals' initial mass did not impair activity levels during a 5 h measurement
period (Moran et al., 1998
)
supporting the observation that energy expenditure was not influenced by the
additional weight. These different observations suggest that the site of
implantation (intraperitoneal versus subcutaneous) might have an
impact on physical activity and overall energy expenditure. Intraperitoneal
implantation seems rather more likely to impair physical performance and
energy expenditure than subcutaneous implantation. In addition, studies in
humans carrying additional weights suggested that an increase in energy
expenditure occurs only if a certain mass threshold is obtained, usually
higher than 10% of initial body mass
(Maloiy et al., 1986
;
Jones et al., 1987
). Possibly,
artificial augmentation of body mass by 10% in mice in the present study lies
below this threshold and thus fails to increase energy expenditure due to
increased physical work required to move the body.
Data on changes of energy expenditure and physical activity following weight implantation remain contradictory, depending on the species, implant mass, and site of implantation, and need further investigation. In addition, direct measurements, e.g. by use of cages equipped with infrared beams, could be more useful for evaluation of physical activity than a calculation of PAL.
The gender-specific differences in body mass point to different strategies
in males and females to cope with a situation affecting energy demands and
body mass. There are a several rodent and human studies to support this
suggestion. In addition to gender-specific responses in energy balance under
hypergravity conditions as mentioned above, different catecholamine responses
to space flight, i.e. in microgravity, have been reported in male and female
astronauts (Stein and Wade,
2001), pointing to gender-specific hormonal effects on body mass
regulation. Gender specific responses were also reported in rats subjected to
a change in energy expenditure by forced and voluntary exercise. Male rats
decreased body mass under the influence of forced exercise whereas female rats
increased energy intake and thereby maintained their body mass
(Nance et al., 1977
;
Cortright et al., 1997
).
Interestingly, similar effects were observed in humans subjected to different
levels of weekly fitness training. Despite an increased daily energy
expenditure, men did not increase energy intake to compensate for the energy
loss (Stubbs et al., 2002a
),
while women at least partially increased their energy intake
(Stubbs et al., 2002b
). In the
present study, HI females showed a more efficient gain in body mass (both
MTB and MBB) compared to HI males,
although energy intake was not significantly increased in HI females compared
to SO and LO females. This implies a higher efficiency of energy utilization
and conservation of females compared to males. This seems reasonable
considering the main evolutionary responsibility of females for reproduction
(Cortright and Koves, 2000
;
Hoyenga and Hoyenga, 1982
) and
the necessity to maintain adequate energy stores throughout gestation and
suckling period. It was suggested that this higher efficiency is a result of
higher selection pressures on females during evolutional development
(Cortright and Koves,
2000
).
Another interesting, gender-specific phenomenon is our observation that LO females showed increased MBB in the second half of the study period compared to SO and HI females and also displayed the highest mean fat increase after 14 weeks. Obviously, in females but not in males the implant volume has an impact on energy balance. It is conceivable that the implant leads to an abdomen distension similar to that experienced during gestation, causing metabolic responses to maintain and increase energy stores rather than to maintain a certain body mass set-point, which in our model would mean to decrease energy stores. During gestation this regulation would ensure an adequate energy supply for the offspring. It is therefore possible that there are two different systems competing with each other: mass-specific set-point regulation of body mass overlapping with a volume-specific response that increased energy resources supposedly by mimicking gestation. The latter should be female-specific and hence would not appear in males.
Conclusions
We found gender-specific responses following an acute, artificial body mass
increase. Perception of body mass per se and a compensatory decrease
in MBB following artificial body mass augmentation
appeared only partially and in males rather than in females. This compensation
happened mainly at the expense of fat mass; lean body mass was maintained at
basal levels in both genders. Long-term energy intake was not affected by the
weight implantation. Also measurements of energy expenditure revealed no
significant influence on body mass, possibly because the sensitivity of the
measurement was insufficient to detect the range of actual changes. In females
the volume of the implanted weight seemed to have a more important impact on
body mass development than the actual weight. It therefore seems that body
mass per se might not be a major player in the set-point regulation
of body mass. In females especially, the distension of the peritoneum induced
by the volume of the weight could have caused the observed gender-specific
body mass development. The real influence of this suggestion could be further
investigated by implanting weights into other sites of the body different from
the peritoneum. Overall, our results do not support the set-point theory of
body mass control with weight per se being regulated. It seems that
different compartments of body mass are perceived and regulated differently.
Notably, the strict conservation of lean body mass compared to the evident
changes in body fat mass suggests that the ponderostat is rather linked to
lean body mass, thus arguing against a predominant lipostatic regulation of
body mass.
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Acknowledgments |
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