animals : generation of the hgh transgenic rats has been described 
 previously . in this study , male transgenic ( tg ) 
 rats and their male wild type ( wt ) littermates were used .
the number of pups per mother was 
 controlled to seven , and the pups were weaned at 21 days of age . after weaning , 4 male rats 
 were maintained in one cage until used for experiments .
they were housed in a room at 23c 
 with a lightning condition of 12-hr light and 12-hr darkness ( lights on at 0800 hr ) . 

laboratory chow ( labo mr standard , nihon nousan co. , yokohama , japan ) and water were 
 provided ad libitum .
all animal experiments performed in this study were 
 according to the guide for the care and use of laboratory animals , the university of tokyo , 
 and approved by the institutional animal care and use committee of the university of 
 tokyo .
experiment 1 : at 4 weeks of age , tg and wt rats were transferred to 
 individual running wheel cages ( indicated as tg - rw ( + ) , n=4 , and wt - rw ( + ) , n=4 , 
 respectively ) or normal plastic cages ( indicated as tg - rw (  ) , n=4 , and wt - rw (  ) , n=4 , 
 respectively ) and maintained for 12 weeks .
the size of the normal plastic cage is 28  44  
 20.5 cm .
the running wheel cage was equipped with a running wheel ( diameter 32 cm and width 
 10 cm ) and a home cage ( 38  28  38 cm ) , and the rats were allowed free access to the 
 wheel . the amount of food intake , body weight and running distance were measured every week . 

pre - weighed aliquots of food were placed on the lids of the cages , and water was supplied by 
 water bottle .
the weight of laboratory chows was measured every same day of the week at the 
 same time 1,200 hr , and the difference of the weight compared to the previous data was 
 regarded as the amount of food intake . crumbled chows were not collected and counted . only the running distance in the running wheel
( kori seiki , tokyo , japan ) . at the end of the experiment , 

rats were removed from the cages and killed by decapitation 12 hr before the lights were 
 turned off .
pituitary glands , intra - thoracic organs , intra - abdominal organs and leg skeletal 
 muscles were weighed , and femoral lengths were measured .
trunk blood was collected at the 
 time of decapitation , and edta2na was added ( 1.25 mg / ml blood ) .
the 
 collected blood was kept on ice and centrifuged at 1,200  g at 4c for 15 
 min .
plasma leptin concentration was measured by 
 using a leptin elisa kit ( morinaga institute of biological science , yokohama , japan ) .
the 
 intra - assay precisions ( as%cv ) of this system were less than 10% .
experiment 2 : based on the results obtained from experiment 1 , we 
 conducted an additional experiment . at 8 weeks of age , tg rats were transferred to 
 individual running wheel cages ( indicated as tg - rw ( + ) , n=8 ) or normal plastic cages 
 ( indicated as tg - rw (  ) , n=5 ) and maintained as described above . after four weeks of free 
 access to the running wheel ,
half of tg - rw ( + ) had their running wheels locked ( indicated as 
 tg - rw ( + ) -locked , n=4 ) .
after four weeks , peripheral 
 blood and cerebrospinal fluid ( csf ) were taken for evaluation of human gh levels .
peripheral 
 blood was collected via tail vein and centrifuged at 1,200  g at 4c for 
 15 min , and the plasma was stored at 20c until use .
csf was sampled by the way as 
 described previously   and stored at 20c until 
 use .
human gh concentrations were measured by using a hgh elsia kit ( alpha diagnostic 
 international , san antonio , tx , u.s.a . ) .
the intra - assay precisions ( as%cv ) of this system 
 were less than 12% .
statistics : the data are presented as the means  sem for each 
 experimental group .
statistical differences between groups were evaluated using student s 
 t test with bonferroni corrections or anova followed by tukey - kramer s 
 test .
running distances are considerably different between wt and tg rats : to 
 determine whether there are any differences in running activity between wt and tg rats , we 
 measured their running distances under free access to running wheel .
running distances 
 varied among individuals and ages in both wt - rw ( + ) and tg - rw ( + ) ( fig .
1afig . 1.running distances in wt - rw ( + ) and tg - rw ( + ) rats .
( a ) individual running distance 
 ( meters per week ) in wt and tg rats from 4 weeks of age .
( b ) the average of running 
 distances in wt - rw ( + ) and tg - rw ( + ) rats from 4 weeks of age .
. however , in tg - rw ( + ) , their overall running distances 
 were gradually decreased after 7 weeks of age and showed significantly less distances 
 compared to wt - rw ( + ) after 11 weeks of age ( fig . 

1b , p<0.05 vs. wt - rw ( + ) , by a student s t 
 test ) .
these results show that innate running activity is considerably different between 
 wt and tg rats .
running distances in wt - rw ( + ) and tg - rw ( + ) rats .
( a ) individual running distance 
 ( meters per week ) in wt and tg rats from 4 weeks of age .
( b ) the average of running 
 distances in wt - rw ( + ) and tg - rw ( + ) rats from 4 weeks of age .
running wheel access decreases body weight gain in both wt and tg rats : 
 we next investigated the changes of body weights in wt and tg rats with or without running 
 wheel ( fig .
the body weight of wt ( a ) and tg ( b ) 
 rats with or without a running wheel was measured every week .
* p<0.05 vs. rw (  ) by a student s t 
 test . ) .
as reported previously [ 5,6,7 , 9 , 11 ] , body 
 weight gain in tg rats was higher than that in wt rats without running wheel access after 
 14 weeks of age ( p<0.0167 , by a student s t test and 
 a bonferroni correction ) .
running wheel access resulted in decreased body weight gain in 
 both wt and tg rats .
compared to wt rats , access to the running wheel had even greater 
 effects on body weight in tg rats .
tg - rw ( + ) showed significantly less body weight 
 compared to wt - rw (  ) from 4 to 12 weeks of age ( p<0.0167 , by a 
 student s t test and a bonferroni correction ) and tg - rw (  ) at all time 
 points examined ( p<0.0167 , by a student s t test and 
 a bonferroni correction ) , and their body weights were similar to those of wt - rw ( + ) at the 
 end of the experiment ( p=0.786 , by a student s t test ) . 

these results show that free access to a running wheel suppresses body weight gain in both 
 wt and tg rats .
the body weight of wt ( a ) and tg ( b ) 
 rats with or without a running wheel was measured every week .
p<0.05 vs. rw (  ) by a student s t 
 test . running wheel access abolishes hyperphagia in tg rats : to examine 

whether the decreased weight gain in both wt and tg rats with running wheel access is 
 accompanied by an alteration of food consumption , their weekly amounts of food intake were 
 measured .
there was no difference in the amounts of food intake between wt - rw (  ) and wt - rw ( + ) throughout the experiment ( fig . 3afig .
( a ) the amount of 
 food intake ( grams per week ) of wt ( a ) and tg ( b ) rats with or without running wheel 
 was measured every week .
* p<0.05 
 vs. tg - rw (  ) by a student s t test . ,
in contrast , in tg rats that exhibit innate hyperphagia 
 ( p<0.0125 vs. wt - rw (  ) , by a student s t test and 
 a bonferroni correction ) , running wheel access significantly decreased their food intakes 
 ( fig .
3b , p<0.0125 , vs. 
 tg - rw (  ) by a student s t test and a bonferroni correction ) .
3a , p>0.0125 , by a student s t test 
 and a bonferroni correction ) . furthermore
, this decreased food consumption was maintained 
 ( p>0.35 , by one - way anova ) until the end of the experiment even 
 after their running distances declined to very low levels ( after 11 weeks of age , figs .
these results indicate that the condition that allows tg rats to access 
 running wheel freely completely abolishes their hyperphagia .
( a ) the amount of 
 food intake ( grams per week ) of wt ( a ) and tg ( b ) rats with or without running wheel 
 was measured every week .
p<0.05 
 vs. tg - rw (  ) by a student s t test .
body compositions and serum leptin levels are changed by running wheel 
 access : suppressed body weight gain by free access to a running wheel was 
 observed in both wt and tg rats . to identify which organs are responsible for the 
 decreased body weight gain ,
the results are 
 shown in table 1table 1.organ weights , femoral lengths and serum leptin levels at 16 weeks of 
 agewt - rw ( )wt - rw ( + ) tg - rw ( )tg - rw ( + ) pituitary gland ( mg)10.28  0.989.93  0.844.28  0.444.58  0.15heart ( g)1.60  0.061.53  0.112.06  0.101.46  0.10lung ( g)2.08  0.251.71  0.062.09  0.171.53  0.10spleen ( g)1.13  0.060.78  0.021.09  0.160.71  0.08kidney ( g)4.36  0.263.63  0.074.26  0.202.94  0.22stomach ( g)2.00  0.092.16  0.232.28 
0.142.12  0.07small intestine ( g)8.46  0.627.92  0.909.48  0.868.70  0.84large intestine ( g)3.01  0.112.99  0.194.12  0.333.26  0.15liver ( g)19.02  1.6813.57  0.4322.96  1.7414.96  1.63cranial tibial ( g)1.39  0.091.26  0.071.00  0.040.91  0.05extensor digitorum longus ( g)0.41  0.020.35  0.010.27  0.020.26  0.01soleus ( g)0.33  0.020.27  0.010.31  0.010.25  0.02femoral length ( mm)38.20  0.2836.67  0.2935.48  0.4534.39  0.78epididymal fat ( g)8.58  1.432.27  0.1917.49  0.3310.79  1.97serum leptin ( ng / ml)14.52
a ) p<0.05 vs. wt - rw (  ) and b ) 
 p<0.05 vs. tg - rw (  ) , respectively , by a tukey - kramer 's 
 test . under the condition without running wheel access , weights of pituitary 
 glands , cranial tibial muscle , extensor digitorum longus muscle and femoral length of tg 
 rats were significantly lower than those of wt rats ( p<0.05 vs. wt - rw 
 (  ) , by tukey - kramer s test ) , whereas those of heart , large intestine and liver were 
 higher than those of wt rats ( p<0.05 vs. wt - rw (  ) , by tukey - kramer s 
 test ) .
in wt rats , only soleus muscle and epididymal fat 
 pad weights decreased after being kept in running wheel cages ( p<0.05 
 vs. wt - rw (  ) , by tukey - kramer s test ) . in tg rats , on the other hand , in addition to 
 soleus muscle and epididymal fat pad , significantly decreased weights were also observed 
 in heart , kidney and large intestine ( p<0.05 vs. tg - rw (  ) , by 
 tukey - kramer s test ) .
these results indicate that free access to a running wheel causes 
 great body composition changes in tg rats .
a ) p<0.05 vs. wt - rw (  ) and b ) 
 p<0.05 vs. tg - rw (  ) , respectively , by a tukey - kramer 's 
 test locking running wheel results in immediate increase of food intake and body 
 weight in tg rats : to examine whether the decreased food intake and body weight 
 gain in tg rats with free access to running wheels persist even after the wheels are 
 fixed , we locked the running wheels and measured the amounts of food intake and body 
 weight .
food intake increased immediately after locking running wheels , and tg - rw 
 ( + ) -locked rats consumed similar amounts of food compared to tg - rw (  ) rats ( fig .
4.effect of locking running wheel on food intake and body weight in tg - rw ( + ) rats . 

half of the running wheels was locked after four weeks of free access to running 
 wheels .
the amount of food intake ( a ) and body weight ( b ) was measured every week . 

* p<0.05 vs. tg - rw (  ) by a 
 tukey - kramer s test . , p>0.05 , by a tukey - kramer s test ) .
body weights of tg - rw 
 ( + ) -locked rats also increased soon after the locking of running wheels and reached 
 similar levels to those of tg - rw (  ) at the end of the experiment ( fig .
these results revealed that the effect of running wheel access on food intake and body 
 weight in tg rats disappears immediately when their free running becomes impossible .
effect of locking running wheel on food intake and body weight in tg - rw ( + ) rats . 

half of the running wheels was locked after four weeks of free access to running 
 wheels .
the amount of food intake ( a ) and body weight ( b ) was measured every week . 

values are means  sem ( n=4 to 5 ) . * p<0.05 vs. tg - rw (  ) by a 
 tukey - kramer s test .
concentrations of hgh in tg rats are unaffected by running wheels : it 
 has been demonstrated that gh overexpression in the central nervous system results in 
 hyperphagia and obesity .
our preliminary study 
 showed that hgh concentrations in csf are over 100-fold higher than the serum 
 concentrations due to the nature of wap promoter included in transgene in tg rats ( data 
 not shown ) .
given these studies , it is possible that free access to running wheels 
 affected wap promoter and then induced decreased hgh concentrations in csf .
thus , we 
 compared hgh levels in csf and serum between tg rats with and without running wheel 
 access .
there was no difference in hgh concentrations in both csf ( 1,150  205 
 ng / ml in tg - rw (  ) vs. 944  55 ng / ml in tg - rw ( + ) ) and serum ( 1.92  0.4 
 ng / ml in tg - rw (  ) vs. 3.9  0.4 
 ng / ml in tg - rw ( + ) ) ( means  sem , n=5 and 4 , 
 respectively ) .
these results indicate that the effects of running wheels on food intake 
 and body weight of tg rats are not due to the changes in the hgh concentrations .
running distances are considerably different between wt and tg rats : to 
 determine whether there are any differences in running activity between wt and tg rats , we 
 measured their running distances under free access to running wheel .
running distances 
 varied among individuals and ages in both wt - rw ( + ) and tg - rw ( + ) ( fig .
1afig . 1.running distances in wt - rw ( + ) and tg - rw ( + ) rats .
( a ) individual running distance 
 ( meters per week ) in wt and tg rats from 4 weeks of age .
( b ) the average of running 
 distances in wt - rw ( + ) and tg - rw ( + ) rats from 4 weeks of age .
. however , in tg - rw ( + ) , their overall running distances 
 were gradually decreased after 7 weeks of age and showed significantly less distances 
 compared to wt - rw ( + ) after 11 weeks of age ( fig . 

1b , p<0.05 vs. wt - rw ( + ) , by a student s t 
 test ) .
these results show that innate running activity is considerably different between 
 wt and tg rats .
running distances in wt - rw ( + ) and tg - rw ( + ) rats .
( a ) individual running distance 
 ( meters per week ) in wt and tg rats from 4 weeks of age .
( b ) the average of running 
 distances in wt - rw ( + ) and tg - rw ( + ) rats from 4 weeks of age .
running wheel access decreases body weight gain in both wt and tg rats : 
 we next investigated the changes of body weights in wt and tg rats with or without running 
 wheel ( fig .
the body weight of wt ( a ) and tg ( b ) 
 rats with or without a running wheel was measured every week .
* p<0.05 vs. rw (  ) by a student s t 
 test . ) .
as reported previously [ 5,6,7 , 9 , 11 ] , body 
 weight gain in tg rats was higher than that in wt rats without running wheel access after 
 14 weeks of age ( p<0.0167 , by a student s t test and 
 a bonferroni correction ) .
running wheel access resulted in decreased body weight gain in 
 both wt and tg rats .
compared to wt rats , access to the running wheel had even greater 
 effects on body weight in tg rats .
tg - rw ( + ) showed significantly less body weight 
 compared to wt - rw (  ) from 4 to 12 weeks of age ( p<0.0167 , by a 
 student s t test and a bonferroni correction ) and tg - rw (  ) at all time 
 points examined ( p<0.0167 , by a student s t test and 
 a bonferroni correction ) , and their body weights were similar to those of wt - rw ( + ) at the 
 end of the experiment ( p=0.786 , by a student s t test ) . 

these results show that free access to a running wheel suppresses body weight gain in both 
 wt and tg rats .
the body weight of wt ( a ) and tg ( b ) 
 rats with or without a running wheel was measured every week .
p<0.05 vs. rw (  ) by a student s t 
 test . running wheel access abolishes hyperphagia in tg rats : to examine 

whether the decreased weight gain in both wt and tg rats with running wheel access is 
 accompanied by an alteration of food consumption , their weekly amounts of food intake were 
 measured .
there was no difference in the amounts of food intake between wt - rw (  ) and wt - rw ( + ) throughout the experiment ( fig . 3afig .
( a ) the amount of 
 food intake ( grams per week ) of wt ( a ) and tg ( b ) rats with or without running wheel 
 was measured every week .
* p<0.05 
 vs. tg - rw (  ) by a student s t test . ,
in contrast , in tg rats that exhibit innate hyperphagia 
 ( p<0.0125 vs. wt - rw (  ) , by a student s t test and 
 a bonferroni correction ) , running wheel access significantly decreased their food intakes 
 ( fig .
3b , p<0.0125 , vs. 
 tg - rw (  ) by a student s t test and a bonferroni correction ) .
3a , p>0.0125 , by a student s t test 
 and a bonferroni correction ) . furthermore
, this decreased food consumption was maintained 
 ( p>0.35 , by one - way anova ) until the end of the experiment even 
 after their running distances declined to very low levels ( after 11 weeks of age , figs .
these results indicate that the condition that allows tg rats to access 
 running wheel freely completely abolishes their hyperphagia .
( a ) the amount of 
 food intake ( grams per week ) of wt ( a ) and tg ( b ) rats with or without running wheel 
 was measured every week .
p<0.05 
 vs. tg - rw (  ) by a student s t test .
body compositions and serum leptin levels are changed by running wheel 
 access : suppressed body weight gain by free access to a running wheel was 
 observed in both wt and tg rats . to identify which organs are responsible for the 
 decreased body weight gain ,
the results are 
 shown in table 1table 1.organ weights , femoral lengths and serum leptin levels at 16 weeks of 
 agewt - rw ( )wt - rw ( + ) tg - rw ( )tg - rw ( + ) pituitary gland ( mg)10.28  0.989.93  0.844.28  0.444.58  0.15heart ( g)1.60  0.061.53  0.112.06  0.101.46  0.10lung ( g)2.08  0.251.71  0.062.09  0.171.53  0.10spleen ( g)1.13  0.060.78  0.021.09  0.160.71  0.08kidney ( g)4.36  0.263.63  0.074.26  0.202.94  0.22stomach ( g)2.00  0.092.16  0.232.28 
0.142.12  0.07small intestine ( g)8.46  0.627.92  0.909.48  0.868.70  0.84large intestine ( g)3.01  0.112.99  0.194.12  0.333.26  0.15liver ( g)19.02  1.6813.57  0.4322.96  1.7414.96  1.63cranial tibial ( g)1.39  0.091.26  0.071.00  0.040.91  0.05extensor digitorum longus ( g)0.41  0.020.35  0.010.27  0.020.26  0.01soleus ( g)0.33  0.020.27  0.010.31  0.010.25  0.02femoral length ( mm)38.20  0.2836.67  0.2935.48  0.4534.39  0.78epididymal fat ( g)8.58  1.432.27  0.1917.49  0.3310.79  1.97serum leptin ( ng / ml)14.52
a ) p<0.05 vs. wt - rw (  ) and b ) 
 p<0.05 vs. tg - rw (  ) , respectively , by a tukey - kramer 's 
 test . under the condition without running wheel access , weights of pituitary 
 glands , cranial tibial muscle , extensor digitorum longus muscle and femoral length of tg 
 rats were significantly lower than those of wt rats ( p<0.05 vs. wt - rw 
 (  ) , by tukey - kramer s test ) , whereas those of heart , large intestine and liver were 
 higher than those of wt rats ( p<0.05 vs. wt - rw (  ) , by tukey - kramer s 
 test ) .
in wt rats , only soleus muscle and epididymal fat 
 pad weights decreased after being kept in running wheel cages ( p<0.05 
 vs. wt - rw (  ) , by tukey - kramer s test ) . in tg rats , on the other hand , in addition to 
 soleus muscle and epididymal fat pad , significantly decreased weights were also observed 
 in heart , kidney and large intestine ( p<0.05 vs. tg - rw (  ) , by 
 tukey - kramer s test ) .
these results indicate that free access to a running wheel causes 
 great body composition changes in tg rats .
a ) p<0.05 vs. wt - rw (  ) and b ) 
 p<0.05 vs. tg - rw (  ) , respectively , by a tukey - kramer 's 
 test
locking running wheel results in immediate increase of food intake and body 
 weight in tg rats : to examine whether the decreased food intake and body weight 
 gain in tg rats with free access to running wheels persist even after the wheels are 
 fixed , we locked the running wheels and measured the amounts of food intake and body 
 weight .
food intake increased immediately after locking running wheels , and tg - rw 
 ( + ) -locked rats consumed similar amounts of food compared to tg - rw (  ) rats ( fig .
4.effect of locking running wheel on food intake and body weight in tg - rw ( + ) rats . 

half of the running wheels was locked after four weeks of free access to running 
 wheels .
the amount of food intake ( a ) and body weight ( b ) was measured every week . 

p<0.05 vs. tg - rw (  ) by a 
 tukey - kramer s test . , p>0.05 , by a tukey - kramer s test ) .
body weights of tg - rw 
 ( + ) -locked rats also increased soon after the locking of running wheels and reached 
 similar levels to those of tg - rw (  ) at the end of the experiment ( fig .
4b , p>0.05 , by a tukey - kramer s test ) . 
 these results revealed that the effect of running wheel access on food intake and body 
 weight in tg rats disappears immediately when their free running becomes impossible .
effect of locking running wheel on food intake and body weight in tg - rw ( + ) rats . 

half of the running wheels was locked after four weeks of free access to running 
 wheels .
the amount of food intake ( a ) and body weight ( b ) was measured every week . 

p<0.05 vs. tg - rw (  ) by a 
 tukey - kramer s test .
concentrations of hgh in tg rats are unaffected by running wheels : it 
 has been demonstrated that gh overexpression in the central nervous system results in 
 hyperphagia and obesity .
our preliminary study 
 showed that hgh concentrations in csf are over 100-fold higher than the serum 
 concentrations due to the nature of wap promoter included in transgene in tg rats ( data 
 not shown ) .
given these studies , it is possible that free access to running wheels 
 affected wap promoter and then induced decreased hgh concentrations in csf . thus , we 
 compared hgh levels in csf and serum between tg rats with and without running wheel 
 access .
there was no difference in hgh concentrations in both csf ( 1,150  205 
 ng / ml in tg - rw (  ) vs. 944  55 ng / ml in tg - rw ( + ) ) and serum ( 1.92  0.4 
 ng / ml in tg - rw (  ) vs. 3.9  0.4 
 ng / ml in tg - rw ( + ) ) ( means  sem , n=5 and 4 , 
 respectively ) .
these results indicate that the effects of running wheels on food intake 
 and body weight of tg rats are not due to the changes in the hgh concentrations .
in the present study , free access to running wheels completely abolished hyperphagia and 
 obesity in tg rats , and this effect persisted for many weeks as far as the running wheel is 
 accessible .
the present result indicated that free access to running wheel suppresses body weight gain 
 in both wt and tg rats .
however , the major factor that mediates the effect of running wheel 
 on body weight gain appears to be different between wt and tg rats , because the running 
 distance of these two rats was significantly different .
increased exercise due to wheel 
 running may account for the weight loss by increasing energy expenditure in wt rats , while 
 the disappearance of hyperphagia caused by wheel running may account for the weight loss by 
 decreasing energy intake in tg rats .
our findings indicate that free access to running wheels completely abolishes hyperphagia 
 in tg rats .
their declined amount of food intake was similar to that of wt rats , but never 
 exceeded to the level less than the amount of wt rats . and
, this effect persists for many 
 weeks as far as the access to the running wheel is possible .
it was reported in rats that 
 the amount of food intake decreases when they have access to running wheels [ 1 , 3 , 4 ] , however , this decrease is seen only transiently and 
 the amounts of food intake gradually return to similar or even higher level than those of 
 rats without running wheels [ 1 , 3 ] .
similar temporal decrease of food intake was observed in our tg rats 
 and their wt littermates when they started voluntary running at 10 weeks of age ( data not 
 shown ) .
however , after the initial period , food consumption of tg rats did not return to 
 their original amounts and remained at a similar level to those of wt rats , while the amount 
 of food intake returned to the original level in wt rats .
we do not have any available data 
 to explain why the temporal decrease of food intake was not observed when we kept rats in 
 running wheel cages from 4 weeks of age .
thus , our results suggest that the amount of food intake is intrinsically 
 programmed in some unknown mechanism in rats , and free access to running wheels has ability 
 to normalize the feeding behavior of tg rats .
previous studies investigated the long - term effects of running wheel access on food 
 consumption using hyperphagic rats .
otsuka 
 long - evans tokushima fatty ( oletf ) rats , lacking cholecystokinin receptors , showed temporal 
 decrease of food consumption only in the initial period of wheel access , while zucker fatty rats , which have a leptin receptor 
 missense mutation , did not change their food consumption throughout the experiment . in tg rats , leptin resistance ,
high peripheral ghrelin levels and increased transport of neuropeptide 
 y ( npy ) from the arcuate nucleus ( arc ) to paraventricular nucleus ( pvn ) of the hypothalamus 
  are suspected as the causation of the 
 hyperphagia .
therefore , the different outcomes observed as to the effect of running wheel on 
 food consumption may be attributable to the different causes of hyperphagia .
further studies 
 are needed to explore the principal cause of hyperphagia in tg rats and detailed mechanisms 
 how running wheels change their feeding behavior .
it was rather surprising that hyperphagia in tg rats was suppressed in spite of their 
 significantly less running distances than wt rats .
this indicates that in tg rats , even the 
 marginal amounts of running distance are sufficient to normalize their food consumption . 

this raises the possibility that rearing environment , which enables them to access to a 
 running wheel anytime , is more important rather than the amounts of physical exercises . in 
 recent years ,
the number of studies on  environmental enrichment  for laboratory rodents is 
 increasing [ 10 , 21 ] .
environmental enrichment is a term for exposing laboratory animals to 
 physical and / or social stimulation that is greater than what they would receive under 
 standard housing conditions [ 18 , 21 ] , and running wheels are considered to function as a 
 physical environmental enrichment factor .
in addition to improvement of animal well - being , 
 it is shown that environmental enrichment affects many kinds of neurochemistry and resulting 
 behaviors , such as neurogenesis , neural plasticity and drug abuse .
some studies how environmental enrichment affects the eating 
 behavior of not only laboratory animals but also farm or zoo animals are being investigated . 

for example , the mice from enriched conditions ( nest box , plastic tube and wood grawing 
 block ) consumed more food than the mice from standard housing conditions .
japanese macaques ( macaca fuscata ) 
 showed a decreased feeding rate ( unit food / min ) when they were housed in wide forested 
 enclosures than in narrow nonvegetated enclosures .
it is possible that the 
 running wheel in our condition acted as environmental enrichment , and this feature inhibited 
 hyperphagia in tg rats .
thus , it is worth examining whether any other environmental 
 enrichment factors ( e.g. , chew woods , tunnel tubes and other toys ) can normalize hyperphagia 
 in tg rats . in conclusion ,
the present results demonstrate that free access to running wheels 
 completely abolishes hyperphagia in tg rats .
furthermore , it is suggested that rearing 
 environment , which enables them to access to a running wheel anytime , rather than the amount 
 of physical exercises is playing the dominant role in this effect .
this may have 
 implications for developing novel therapeutic approach for controlling hyperphagia to 
 prevent obesity .
 abstractobesity is a major health problem , and increased food intake and decreased 
 physical activity are considered as two major factors causing obesity . 
 previous studies 
 show that voluntary exercise in a running wheel decreases not only body weight but also 
 food intake of rats . 
 we previously produced human growth hormone transgenic ( tg ) rats , 
 which are characterized by severe hyperphagia and obesity . 
 to gain more insight into the 
 effects on physical activity to food consumption and obesity , we examined whether 
 voluntary running wheel exercise causes inhibition of hyperphagia and alteration of body 
 composition in tg rats . 
 free access to running wheels completely abolished hyperphagia in 
 tg rats , and this effect persisted for many weeks as far as the running wheel is 
 accessible . unexpectedly , though the running distances of tg rats were significantly less 
 than those of wild type rats , it was sufficient to normalize their food consumption . 
 this 
 raises the possibility that rearing environment , which enables them to access to a running 
 wheel freely , rather than the amounts of physical exercises is more important for the 
 maintenance of proper food intake . 
MATERIALS AND METHODS
RESULTS
Results 1
Results 2
DISCUSSION