Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
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ABSTRACT |
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The effects of intracranial transforming
growth factor (TGF)-3 on spontaneous motor activity and energy
metabolism were examined in rats. After injection of TGF-
3 into the
cisterna magna of the rat, spontaneous motor activity decreased
significantly for 1 h. The intracranial injection of TGF-
3
produced an immediate decrease in respiratory exchange ratio (RER). No
significant changes were observed in energy expenditure. TGF-
3
induced a significant increase in total fat oxidation and a decrease in
total carbohydrate oxidation. Furthermore, the serum substrates
associated with fat metabolism were significantly altered in rats
injected with TGF-
3. Both lipoprotein lipase activity in skeletal
muscle and the concentration of serum ketone bodies increased,
suggesting that the increase in fat oxidation caused by TGF-
3 may
have occurred in the liver and muscle. Intracranial injection of
TGF-
3 appeared to evoke a switch in the energy substrates accessed
in energy expenditure. These results suggest that the release of
TGF-
3 in the brain by exercise is a signal for regulating energy consumption.
spontaneous motor activity; respiratory exchange ratio; energy metabolism
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INTRODUCTION |
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WE HAVE PREVIOUSLY
REPORTED that intracranial administration of cerebrospinal fluid
(CSF) from exercise-exhausted rats produced a decrease in spontaneous
motor activity, whereas CSF from sedentary rats had no such effect
(19). The substance that regulates the urge for motion in
response to exercise exhaustion was identified as transforming growth
factor- (TGF-
) (23, 24). Growing evidence indicates
that accumulation of the active forms of TGF-
2 and/or TGF-
3 in
the brain is involved in the fatigue induced by exercise (19, 20,
23).
The sensation of fatigue in the brain, however, may not merely be an
inconvenience but may constitute a physiological defense mechanism
against total exhaustion. If this is so, the active forms of TGF-
found in the brain may function positively to prevent peripheral
exhaustion and to enhance recovery.
The brain may detect changes in the normal levels of the constituents of the blood, such as the concentration ratio of tryptophan to branched-chain amino acids (4, 6, 7, 11, 12, 26-29), which can then act as a specific signal to increase the organism's sensitivity to fatigue. However, little is known about the counteractive effects of the central nervous system (CNS) on peripheral energy metabolism.
After exercise exhaustion, the respiratory exchange ratio is usually lower for a more extended period than it is before exercise, although oxygen consumption returns readily to its preexercise level (5, 32). This suggests that the sensation of fatigue affects not only spontaneous motor activity but also energy metabolism, i.e., it enhances fat oxidation to conserve glucose. It seems reasonable to suppose that the substances released in the brain that accompany fatigue may regulate energy metabolism and induce the restoration of energy resources.
We have reported that the intracranial administration of TGF-3
suppresses spontaneous motor activity in mice without substantial exercise loading (20) and may affect peripheral energy
metabolism. The TGF-
s represent a multifunctional family of
cytokines with three closely related isoforms: TGF-
1, TGF-
2, and
TGF-
3. These isoforms are expressed in several cell types of the
CNS, including neurons, astrocytes, and microglia (9).
Unsicker et al. (36) reported that TGF-
2 and TGF-
3
mRNAs are present in all brain areas, including the cerebral cortex,
hippocampus, striatum, cerebellum, and brain stem. In this study, we
used TGF-
3 to represent the TGF-
isoforms for the following
reasons. We have found that TGF-
2 and TGF-
3 suppress spontaneous
motor activity equally, and a considerably higher dose of TGF-
1 is
required to exert a suppressive effect equal to that required for
either TGF-
2 or TGF-
3 (20). TGF-
2 and TGF-
3
are ubiquitously abundant in the rat brain (36), and we
have confirmed that TGF-
1 and TGF-
2 levels do not change in the
brain, even when total TGF-
levels increase (unpublished data). In the present study, we demonstrate that injection of TGF-
3 into the brain alters peripheral energy metabolism to resemble that induced during exercise exhaustion.
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MATERIALS AND METHODS |
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Animals and diets. Male Sprague-Dawley rats (8 wk old, Japan Charles River, Yokohama, Japan) were used in the present study. All animals were maintained on an inverse 18:6-h light-dark cycle (light on for 18 h, and light off for 6 h) for 1 wk to make them active during the experimental time. They were individually housed in standard cages (25 × 38 × 17.5 cm; one rat per cage) under controlled conditions. Room temperature and humidity were regulated at 22 ± 0.5°C and 50%, respectively. During the study period, rats were given free access to water and a high-fat (30%) diet, containing 21 g/kg protein, 30 g/kg fat, and 49 g/kg carbohydrate. All animals were treated humanely as outlined in the National Research Council's Guide for the Care and Use of Laboratory Animals (Kyoto University Animal Care Committee according to NIH #86-23, revised 1985).
Intracranial injection (brain implantation of a guide cannula).
TGF-3 was purchased from R&D Systems (Minneapolis, MN). TGF-
3 (40 ng), dissolved in 40 µl of saline containing 0.5 mM HCl and 0.1%
bovine serum albumin (BSA), was injected into the brains of rats. An
equal volume of vehicle was used as a control. Soon after rats were
purchased, they were anesthetized with 1 mg/kg pentobarbital sodium
(Wako Pure Chemical Industries, Osaka, Japan), fixed onto a stereotaxic
apparatus, and implanted with a permanent 23-gauge guide cannula for
sample injection into the cisterna magna. Each cannula was inserted 2.5 mm posterior to the lambda and 8.5 mm deep, and it inclined anteriorly
at an angle of 45° to the skull surface. The cannula was secured to
the skull with dental cement and then plugged with a cap. After
implantation of the guide cannula, the rats were allowed to recover for
3 days before measurements were made of spontaneous motor activity,
oxygen consumption (
O2), and
CO2 production (
CO2).
Determination of spontaneous motor activity.
The spontaneous motor activity of each rat was examined with a Supermex
(Muromachi Kikai, Tokyo, Japan) for 1 h after intracranial injection of TGF-3. This apparatus surveys the measurement area with
multiple lenses that detect the infrared radiation emitted by animals.
Motor activity was assessed as a single count when the animal moved
from one region of the measurement area, which was optically divided by
the multiple lenses, to a neighboring region. The rats were sedentary
and not subjected to any exercise before measurements were made. The
cages used for measurement were completely novel environments for the rats.
Assessment of metabolic rate.
The respiratory exchange ratio (RER) was measured by indirect
calorimetry. Rats were fasted overnight on the day before the experiments, and food was provided for 1.5 h immediately before the experiments. Rats were placed in the chamber individually before
the experiment for 1 h to maintain RER at a constant value. After
the injection of TGF-3, RER was measured for ~1 h. To determine whether the effects of TGF-
3 on the metabolic rate were specific, 1 µg of thyrotropin-releasing hormone (TRH) (Research Biochemicals Int,
Natick, MA) dissolved in 40 µl of saline was also injected into the brains of rats as a positive control.
Analysis of serum samples.
Blood was collected from severed neck veins, and serum was isolated by
centrifugation and stored at 80°C until analysis. Serum glucose was
measured using the glucose oxidase method combined with mutarotase by
use of glucose AR-II and a commercial kit (Wako Pure Chemical
Industries). Serum free fatty acids (FFA) were measured by an acyl-CoA
synthetase and acyl-CoA oxidase method using NEFA C (Wako Pure Chemical
Industries). Serum triglycerides were assayed by the
glycerol-3-phosphate oxidase method with the triglyceride G test (Wako
Pure Chemical Industries). Serum lactic acid was measured by the
lactate oxidase method using Determiner LA (Kyowa Medics,
Tokyo, Japan). Serum ketone bodies were measured using a ketone
test (Sanwa Chemical Institute, Nagoya, Japan). For the catecholamine
assay, serum samples were purified with aluminum oxide by the method of
Anton and Sayre (1). Serum samples (100 µl) containing
10% Na2S2O5 (50 µl/ml) and
3,4-dihydroxybenzylamide (40 ng/ml) as the internal standards were
added to 100 µl of 2 M Tris · HCl buffer, pH 8.6, and
aluminum oxide (100 mg/ml). The mixture was shaken in a microtube mixer
for 10 min, the supernatant was removed, and the aluminum oxide was
washed twice with methanol and distilled water. Epinephrine and
norepinephrine were eluted with 60 µl of 0.5 N HCl. The eluate was
assayed using an HPLC-electrochemical detector (37). Serum
insulin and leptin were measured using a Mercodia Rat Insulin Kit
(Mercodia, Uppsala, Sweden) and a Morinaga Rat Leptin Kit (Morinaga,
Yokohama, Japan), respectively.
Measurements of muscle lipoprotein lipase activity and serum glycerol concentrations. Gastrocnemius and soleus muscle samples were dissected away from visible fat. Samples (3-10 mg) of skeletal muscle (gastrocnemius) were ground in liquid nitrogen and incubated (in duplicate) in 200 µl of Krebs-Ringer solution, 0.1 M Tris · HCl buffer (pH 8.4) containing 1 g/100 ml of BSA and 2.5 U (50 mg/l) of heparin (35), with gentle shaking at 28°C. After 40 min, the tissue was removed from the medium by centrifugation for 5 min, and the supernatant was used for the measurement of lipoprotein lipase (LPL) activity with an LPL activity kit including a nonfluorescent substrate emulsion that becomes intensely fluorescent upon interaction with LPL (Roar Biomedical, New York, NY). The total protein content of each sample was measured by the Bradford method with Coomassie brilliant blue solution. LPL activity was assessed relative to the protein content of the tissue, and the values are expressed as the ratio of each group to the nontreatment group. Serum glycerol was determined by the ultraviolet method by use of F-kit glycerol (J. K. International, Tokyo, Japan).
Statistics. All data are expressed as means ± SE. Statistical analysis of differences between preinjection and postinjection measurements in the same group was performed with repeated-measures ANOVA test. Dunnett's test was used for post hoc analysis. The means of more than three groups measured at the same point in time were compared by one-way ANOVA followed by Dunnett's test.
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RESULTS |
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Effects of TGF-3 on spontaneous motor activity in rats.
The spontaneous motor activity of the rats was determined with Supermex
for 1 h after the injection of TGF-
3 by detecting the movement
of infrared radiation emanating from the animal every 5 min. The
spontaneous motor activity was gradually suppressed 20 min after
injection in rats treated with TGF-
3 (Fig.
1A). Figure 1B
shows the total spontaneous motor activity for 1 h. Total counts
were calculated by adding up all counts over 5-min periods. The
administration of TGF-
3 significantly suppressed the activity of the
rat.
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Effects of TGF-3 on metabolic rate.
Figure 2 shows the changes in metabolic
rate in rats injected intracranially with vehicle, TGF-
3, or TRH.
The high-fat diet maintained RER at ~0.85 before sample injection. An
injection of 40 ng of TGF-
3 significantly lowered RER compared with
that in the same rat before injection. TGF-
3 significantly reduced the RER of the rat by 7 min after injection, and its effect was maintained for
1 h after injection. The same volume of vehicle injected as a control reduced the RER slightly. During the experiment, rats were deprived of access to food for 2 h and, therefore, RER was naturally reduced.
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Changes in serum energy substrates and concentrations of hormones
after injection with TGF-3.
Serum concentrations of glucose and lactic acid, which are
affected by carbohydrate oxidation, had not changed 14 and 28 min after
injection in either the TGF-
3 or vehicle group (Fig.
6, A and B). The
concentrations of the serum parameters associated with fat oxidation
(FFA, triglycerides, and ketone bodies) were measured (Fig. 6,
C-E). The concentrations of serum FFA in the vehicle group had decreased significantly at 28 min compared with those
at 14 min, but no change was observed in the TGF-
3 group. Therefore,
the serum FFA concentrations in the TGF-
3 group were apparently
higher than those in the vehicle group. Triglyceride concentrations in
the TGF-
3 group were lower than those in the vehicle group at 14 min. The concentration of ketone bodies increased significantly in the
TGF-
3 group. These results suggest that intracranial injection of
TGF-
3 significantly facilitated fat oxidation and tended to restrict
carbohydrate oxidation, which corresponds to the metabolic condition
after exercise.
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Changes in muscle LPL activity and serum glycerol concentration
after injection of TGF-3.
To determine whether TGF-
3 caused an increase in fat oxidation in
skeletal muscle, LPL activity was estimated. LPL activity in skeletal
muscle, especially the gastrocnemius, is shown in Fig.
8A. In the gastrocnemius, LPL
activity rose significantly 28 min after the injection of TGF-
3. In
the vehicle group, there was no significant increase in LPL activity.
Similar effects of TGF-
3 were also observed in the soleus muscle,
although there was no significant difference compared with the vehicle
group or before injection (data not shown).
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DISCUSSION |
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In previous studies, we have demonstrated that physical exercise
causes an increase in TGF-3 levels in the mouse brain and that
intracranial TGF-
3 injection induces the suppression of spontaneous
motor activity (19, 20). These studies indicated that
TGF-
3 may be associated with the induction of central fatigue during exercise.
In the present study, we investigated the effects of intracranial
injection of TGF-3 on the peripheral metabolism in rats. Intracranial injection of TGF-
3 suppressed spontaneous motor activity in rats and decreased the RER (Figs. 1 and 2), similar to the
corresponding experimentally induced effects in mice. The injection of
TGF-
3 did not cause any toxicity or abnormal behavior in the rats.
One day after injection of TGF-
3, both the spontaneous motor
activity and the RER of every rat were restored to normal (data not shown).
Rats were fed a high-fat diet, which influences the RER. There was the
dispersion in RER value of each rat fed the commercial diet; however,
the RER value stabilized between 0.8 and 0.9 by the high-fat diet. We
used the high-fat diet because RER was more stable, and it facilitated
the comparison between pre- and posttreatment. Also, we used it in
previous experiments and wanted to be able to compare these data to
those generated previously in our laboratory. We have been assured that
there were no differences in the effect of TGF-3 on spontaneous
motor activity and RER of rats between use of a high-fat diet and a
commercial diet.
In general, the blood-brain barrier is highly permeable to water,
carbon dioxide, oxygen, and most lipid-soluble substances and is almost
impermeable to plasma proteins and most non-lipid-soluble large organic
molecules. Accordingly, we speculated that the permeability of TGF-
into the blood-brain barrier might be very low or almost none.
Therefore, we can derive from this premise that TGF-
3 released from
the brain directly affects spontaneous motor activity and the energy
status of the animal. This implies that the effects of TGF-
3 on
peripheral tissues with energy are mediated through the CNS.
Overall, O2 was not altered by the
injection of TGF-
3 (Fig. 3). In this experiment, TRH was injected
into the rat brain as a positive control on the basis of the report by
Griffiths et al. (14) that acute or chronic injection of a
TRH analog (RX-77368) and TRH itself stimulated
O2 in rats (14). They demonstrated that intracranial TRH markedly increased the metabolic rate in rats without any apparent effect on physical activity. TRH is
suggested to have a physiological role in the control of these
phenomena via centralized activity. Hence, TRH injection is an
appropriate procedure with which to verify cannula placement. The
injection of either sample may cause a spike in
O2 in both groups from immediately after
injection to 14 min after injection. Therefore, it would appear that
the injection of either sample may cause some stress to rats. However,
any handling effects were apparent for only the first 14 min, as
indicated by the fact that the
O2 of
vehicle animals returned to basal levels at this time. After this time,
the differences observed should be strictly treatment related.
Short and Sedlock (32) reported that postexercise
RER decreased for 1 h in humans. They reported that RER values were
at or below baseline throughout much of the recovery period but that
O2 immediately reverted to the baseline
levels calculated before exercise. It has also been shown in rats that
RER values decrease 10 min after exercise and that
O2 is restored to basal levels (33). Intriguingly, the peripheral energy status induced
by intracranial injection of TGF-
3 appears to correspond to that induced by exercise. Our findings imply that the intracranial injection
of TGF-
s may replicate energy metabolism after exercise.
Fat oxidation was facilitated by intracranial TGF-3
injection (Fig. 4B). Rats injected with TGF-
3 exhibited
increased serum FFA and ketone body concentrations and decreased serum
triglyceride concentrations compared with the vehicle group, which
suggests that their lipid metabolism was elevated (Fig. 6,
C-E). FFA concentrations in the TGF-
3 group were higher
than in the control group. Usually, fatty acids are seldom supplied
from the triacylglycerol originally presented in blood plasma. Most
FFAs oxidized during exercise are supplied from the triacylglycerol
stored in adipose tissue and muscle (8, 16). Because the
only product of hydrolysis that appears in the blood is glycerol, we
examined whether TGF-
3 actually induced hydrolysis by measuring
serum glycerol. As shown in Fig. 8B, serum glycerol
concentrations tended to increase after intracranial injection of
TGF-
3. From these results, it is reasonable to suppose that TGF-
3
enhances FFA delivery to the muscles. Serum triglyceride concentrations
had decreased by 15 min (Fig. 6D). It is inferred that an
increase in LPL activity in skeletal muscle caused the decrease in
serum triglycerides, which seems to be a consistent and reasonable proposition.
There were no differences in the metabolic parameters associated with
carbohydrate oxidation between the rats injected with vehicle and those
injected with TGF-3 (Fig. 6, A and B).
However, the metabolic parameters associated with fat oxidation changed after injection of TGF-
3. Furthermore, intracranial injection of
TGF-
3 significantly increased LPL activity in skeletal muscle at 28 min after injection (Fig. 8A). Serum ketone body
concentrations increased, indicating that lipid oxidation was enhanced
in the liver. This is because ketone bodies produced in the liver are more easily taken up by skeletal muscle as an energy resource. We
anticipate that TGF-
3 causes an increase in fat oxidation in both
the liver and the muscle. It has been reported that exercise induces
LPL activity in skeletal muscle (22, 31), which would be
necessary to burn the fat efficiently. It is interesting that intracranial injection of TGF-
3 caused LPL activity in skeletal muscle in the same way as exercise.
Leptin levels in rats injected with TGF-3 did not change. It has
been reported that leptin production is not changed by short-term exercise (12, 30). We can suggest that our observation in this study is similar, because no changes in leptin were seen during
short-term exercise.
Hwa and colleagues (17, 18) reported that a single
intracerebroventricular injection of leptin increased energy
expenditure while reducing the respiratory quotient in a dose-dependent
manner. They demonstrated that leptin regulates the energy balance via multiple mechanisms, which was certainly mediated by the
regulation of both food intake and energy metabolism (17,
18). Although both leptin and TGF- augment fat oxidation, our
results suggest that intracranial injection of TGF-
3 does not
directly affect the peripheral leptin levels. How does intracranial
TGF-
increase fat oxidation? Minokoshi et al. (25)
showed that the intrahypothalamic injection of leptin increases the
fatty acid oxidation by activating the 5'-AMP-activated protein kinase
(25). Careful consideration of our results regarding LPL
activity leads us to infer that intracranial injection of TGF-
3
induced an increase in fat oxidation via the sympathetic nervous
system, just as leptin works through the hypothalamic-sympathetic nervous system. However, at the present time, we cannot know whether both TGF-
and leptin modulate fat oxidation via the same neural pathway. Further studies are required to clarify whether there is an
interaction between leptin and TGF-
s in the CNS.
As shown in Fig. 7A, epinephrine concentration tended to
increase at 14 min after treatment with TGF-3. Serum epinephrine concentrations also increase after intense exercise. Tadjore et al.
(34) reported that plasma epinephrine concentrations in rats increased after prolonged swimming. Cooper et al.
(10) demonstrated that blood levels of epinephrine
increase gradually after high- and low-intensity exercise in humans. In
our study, however, the turnover rate of serum catecholamines was
rapid; we suspected that catecholamines had already been
recovered. Serum insulin levels increased in the vehicle group, whereas
they did not change in the TGF-
3 group (Fig. 7C).
Injection of TGF-
3 may suppress an increase in insulin to restrict
fat storage. However, the reasons for the increase in insulin levels in
the vehicle group are unclear.
The muscle LPL activity was increased by TGF-; however, at
this time there is no significant change in norepinephrine levels to
explain this increase (Fig. 8A). Furthermore, despite the
fact that LPL activity no longer increased after 56 min, fat oxidation kept increasing. This might suggest that the activation of LPL is not
critical in this experiment after 56 min. Although we have not studied
the fat oxidation in liver, we anticipated that the lipid oxidation
also increased in liver because of the increase of ketone bodies, and
that it might contribute to continuing fat oxidation after 56 min.
The metabolic changes induced by the injection of TGF-3 are very
similar to the state of energy metabolism after physical exercise.
Because energy expenditure did not change, intracranial injection of
TGF-
3 may cause a switch of energy substrates. During prolonged
exercise, utilization of energy substrates shows a gradual transition
from carbohydrate to fat. Other studies have reported that there is a
significant substrate shift toward fat oxidation after high-intensity
exercise (3, 38). This is a common phenomenon in exercise
physiology, but the complete mechanism of the switch in energy
substrates has not been clarified. TGF-
3 that is released in the
brain during exercise may increase the rate of fat oxidation to
conserve glucose. We also reported that the changes shown by electroencephalogram after intracranial injection of TGF-
were consistent with those after exercise (2). This suggested
that the increase in TGF-
level in the brain is partly relevant to the change of neuronal activity after exercise. It seems reasonable that TGF-
3 released in the brain during exercise suppresses
spontaneous motor activity to encourage rest and causes an alteration
in the energy substrates of the peripheral system.
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ACKNOWLEDGEMENTS |
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We thank Wataru Mizunoya for technical assistance in the measurements of glycerol and LPL activity. We gratefully acknowledge Dr. G. Lynis Dohm of East Carolina University for critical reading and valuable comments.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Fushiki, Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto Univ. Oiwakecho, Kitashirakawa, Sakyo, Kyoto, Japan 606-8502. (E-mail: d53765{at}sakura.kudpc.kyoto-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 28, 2002;10.1152/ajpendo.00094.2001
Received 5 March 2001; accepted in final form 4 May 2002.
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