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Diabetes mellitus induces neuropsychiatric comorbidities at an early stage, which can be ameliorated by exercise. However, the neurobiological mechanisms underlying this ameliorative effect remain unclear. The present study was conducted in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which develop diabetes with age, and aimed to investigate whether social and anxiety-like behaviors and neurobiological changes associated with these behavioral phenotypes were reversed by voluntary exercise and whether those were maintained in the later stage. We investigated the effects of exercise at different diabetic stages in OLETF rats by comparing with control rats. Three groups of OLETF rats were used: sedentary rats, rats exercising on a wheel for two weeks at 4-5 weeks of age (early voluntary exercise), and those exercising at 10-11 weeks of age (late voluntary exercise). In the elevated plus-maze test, both early and late voluntary exercises did not affect anxiety-like behavior. In the social interaction tests, both early and late voluntary exercises ameliorated impaired sociability, novel exploration deficits, and hypoactivity in OLETF rats. Both early and late voluntary exercises reversed the increases in cholecystokinin-positive neuron densities in the infralimbic cortex and hippocampal cornu ammonis area 3 in the OLETF rats, although they did not affect the area-reduction in the medial prefrontal cortex and the increase in cholecystokinin-positive neuron densities in the basolateral amygdala. These suggest that voluntary exercise has therapeutic effects on impaired sociability and novel exploration deficits associated with cholecystokinin-positive neurons in specific corticolimbic regions in OLETF rats, and those are maintained after early exercise.

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.

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.