This study aimed to investigate the influence of childhood exercise and detraining on brown adipose tissue (BAT) whitening in obesity. Four-week-old male Long-Evans Tokushima Otsuka (LETO) rats (n = 9) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 24) were used as non-obese and obese animals, respectively. OLETF rats were divided into non-exercise sedentary (n = 9) and exercise groups. OLETF rats in the exercise group were further divided into subgroups according to the exercise period—exercise from 10- to 12-weeks-old (n = 6); and exercise from 4- to 6-weeks-old, and detraining from 6- to 12-weeks-old (n = 9). At 12-weeks-old, immediately after exercise period, BAT whitening in OLETF rats was inhibited by exercise despite the fact that hypertrophy was not caused in the plantaris muscle. However, the effectiveness was attenuated during the detraining period. Histological BAT whitening and downregulation of uncoupling protein-1 (UCP-1) were found in non-exercise sedentary OLETF rats at 12-weeks-old. The downregulation was not inhibited, even though exercise histologically inhibited BAT whitening in OLETF rats. Childhood exercise decreased BAT whitening in obesity. Detraining attenuated the inhibition of BAT whitening. These results suggest that regular exercise is needed to improve BAT whitening and downregulation of UCP-1 in obesity.

Exercise promotes mitochondrial uncoupling in brown adipose tissue (BAT), which results in browning and accelerated energy metabolism. Because obesity leads to mitochondrial dysfunction with consequential impaired uncoupling, exercise‐induced adipose tissue browning could be inhibited in genetic predisposition to obesity. The purpose of the present study was to investigate the influences of childhood exercise in spontaneous obesity animals focusing on adipose tissue browning. Four‐week‐old male Otsuka Long‐Evans Tokushima fatty (OLETF, 88 ± 4 g body weight) rats and age‐matched male Long‐Evans Tokushima Otsuka (LETO, 82 ± 4 g body weight) rats were used as spontaneous obesity animals and non‐obesity animals, respectively. All rats were divided into the exercise or non‐exercise groups. The rats in the exercise groups were placed in the cages with a running wheel for 12 h (20:00 to 8:00) daily from 4 to 6 weeks of age. Food and water were provided ad libitum. Transverse sections were obtained from interscapular BAT and stained with hematoxylin and eosin for histological observation. In addition, the expression levels of uncoupling protein 1 (UCP1) in BAT were measured by western blotting. White adipocytes with unilocular lipid droplet were widely observed in the BAT of OLETF rats. The enlarged white adipocytes were rarely observed in OLETF rats of the exercise group. Although there were no significant differences in the expression level of UCP1 among the experimental groups, the levels were obviously different between OLETF rats in the exercise group. Total food intake during 12 h of voluntary wheel running was lower in the rat with the high UCP1 expression than in the low expression. Total running distance was higher in the rat with high UCP1 expression than in the low expression. Therefore, higher ratio of the total running distance to total food intake was shown in the OLETF rat with higher UCP1 expression. Exercise in childhood shrank the adipocytes in the BAT, suggesting the effectiveness to prevent pediatric obesity. Additionally, exercise‐induced UCP1 expression could depend on the ratio of exercise to food intake.

Brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. However, the activity declines in obesity due to brown‐to‐white conversion in BAT. Because the properties of adipose tissue are determined before adult, childhood exercise could prevent brown‐to‐white conversion and maintain metabolic activity of BAT in future. The purpose of the present study was to investigate histological influences of childhood exercise and detraining in BAT of genetic predisposition to obesity. Four‐week‐old male Long‐Evans Tokushima Otsuka (LETO) rats and age‐matched male Otsuka Long‐Evans Tokushima fatty (OLETF) rats were used as non‐obesity animals and spontaneous obesity animals, respectively. OLETF rats were divided into the non‐exercise sedentary (OLETF Sed) or exercise groups. OLETF rats in the exercise group were further divided into subgroups according to exercise age. OLETF rats in the exercise groups were placed in the cages with a running wheel for 12 h (20:00 to 8:00) daily from 4 to 6 (OLETF Ex 4‐6 w) or 10 to 12 (OLETF Ex 10‐12 w) weeks of age (i.e. the OLETF Ex 4‐6 w group: exercise from 4 to 6‐week‐old, detraining from 6 to 12‐week‐old; the OLETF Ex 10‐12 w group: non‐exercise from 4 to 10‐week‐old, exercise from 10 to 12‐week‐old). Food and water were provided ad libitum. At 12‐week‐old, transverse sections were obtained from interscapular BAT and stained with hematoxylin and eosin for histological observation. The results at 12‐week‐old were shown below. The wet weights of interscapular BAT were significantly higher in the OLETF Sed group than in LETO rats. The values were significantly lower in the OLETF Ex 10‐12 w group than in the OLETF Sed group. There were no significant differences for the weights between the OLETF Ex 4‐6 w and OLETF Sed groups. Histological observation revealed conversion of brown adipocytes to white‐like unilocular cells in both LETO and OLETF rats. In LETO rats, the white‐like unilocular cells were located uniformly in the fat lobule. In OLETF rats, enlarged white‐like unilocular cells were also observed in the peripheral zone of the lobule. There were no significant differences for the diameters of white‐like unilocular cells located in the central zone of the lobule among the experimental groups. The densities of white‐like unilocular cells located in the central zone of the lobule were significantly lower in the OLETF Ex 10‐12 w group than in the other groups. There were no significant differences for the densities among LETO rats, the OLETF Sed, and OLETF Ex 4‐6 w groups. Childhood Exercise immediately inhibited brown‐to‐white conversion in the BAT and decreased the mass. However, the effectiveness did not be maintained for a long time. These results suggested that chronic exercise is required to maintain adipose tissue browning in genetic predisposition to obesity.

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats.

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