Reduction of Food Intake by Fenofibrate is Associated with Cholecystokinin Release in Long-Evans Tokushima Rats

Fenofibrate is a selective peroxisome proliferator-activated receptor alpha (PPARalpha) activator and is prescribed to treat hyperlipidemia. The mechanism through which PPARalpha agonists reduce food intake, body weight, and adiposity remains unclear. One explanation for the reduction of food intake is that fenofibrate promotes fatty acid oxidation and increases the production of ketone bodies upon a standard experimental dose of the drug (100~300 mg/kg/day). We observed that low-dose treatment of fenofibrate (30 mg/kg/day), which does not cause significant changes in ketone body synthesis, reduced food intake in Long-Evans Tokushima (LETO) rats. LETO rats are the physiologically normal controls for Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are obese and cholecystokinin (CCK)-A receptor deficient. We hypothesized that the reduced food intake by fenofibrate-treated LETO rats may be associated with CCK production. To investigate the anorexic effects of fenofibrate in vivo and to determine whether CCK production may be involved, we examined the amount of food intake and CCK production. Fenofibrate-treated OLETF rats did not significantly change their food intake while LETO rats decreased their food intake. Treatment of fenofibrate increased CCK synthesis in the duodenal epithelial cells of both LETO and OLETF rats. The absence of a change in the food intake of OLETF rats, despite the increase in CCK production, may be explained by the absence of CCK-A receptors. Contrary to the OLETF rats, LETO rats, which have normal CCK receptors, presented a decrease in food intake and an increase in CCK production. These results suggest that reduced food intake by fenofibrate treatment may be associated with CCK production.

Differential Expression of Metabolism-related Genes in Liver of Diabetic Obese Rats

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous type 2 diabetes (T2D), develops hyperglycemic obesity with hyperinsulinemia and insulin resistance after the age of 25 weeks, similar to patients with noninsulin-dependent diabetes mellitus (DM). In the present study, we determined whether there are differences in the pattern of gene expression related to glucose and lipid metabolism between OLETF rats and their control counterparts, Long-Evans Tokushima (LETO) rats. The experiment was done using 35-week-old OLETF and LETO rats. At week 35 male OLETF rats showed overt T2D and increases in blood glucose, plasma insulin, plasma triglycerides (TG) and plasma total cholesterol (TC). Livers of diabetic OLETF and LETO rats also showed differences in expression of mRNA for glucose and lipid metabolism related genes. Among glucose metabolism related genes, GAPDH mRNA was significantly higher and FBPase and G6Pase mRNA were significantly lower in OLETF rats. For lipid metabolism related genes, HMGCR, SCD1 and HL mRNA were substantially higher in OLETF rats. These results indicate that gluconeogenesis in OLETF rats is lower and glycolysis is higher, which means that glucose metabolism might be compensated for by a lowering of the blood glucose level. However, lipid synthesis is increased in OLETF rats so diabetes may be aggravated. These differences between OLETF and LETO rats suggest mechanisms that could be targeted during the development of therapeutic agents for diabetes.

The Effects of Antidepressants on the Energy Metabolism in LETO Rat / 대한정신약물학회지

Objectives : A diverse range of adverse effects has been linked to the application of antidepressants for the treatment of depressive disorder. Recently, evidence has been emerging of the adverse metabolic effects of antidepressants. This study investigated the effects of antidepressants on plasma glucose and other factors in the fat and muscle tissue relating to metabolism. METHODS : Long-Evans-Tokushima-Ostuka (LETO) rats were used to evaluate the effects of different antidepressants. Amitriptyline, fluoxetine, and mirtazapine were administered to each of three subgroups for 4 weeks, between 11 and 15 weeks old, while a fourth subgroup was administered no antidepressant during the same period. Changes of weight and daily intake were monitored. Tissues and blood were collected at 15 weeks. RESULTS : The fluoxetine subgroup showed lower weight gain and lower food efficacy ratio than did the other subgroups. Blood glucose and other circulating factors showed no significant differences among groups, except for the leptin levels of the fluoxetine subgroup. However, the amitriptyline and mirtazapine subgroups showed similar patterns in the response of mRNA expression of peroxisome proliferator-activated receptors gamma cofactor-1 and uncoupling protein-1, 2, 3. CONCLUSION : These results could indicate possible differences in metabolic response based on the kind of antidepressant used.

Expression of Transforming Growth Factor-beta1 in Spontaneously Developed Diabetic Rats / 대한신장학회잡지

BACKGROUND: Diabetic nephropathy is a common cause of end-stage renal disease by means of glomerular and interstitial fibrosis. Increases in extracellular matrix (ECM) and changes in its components have been documented in the glomeruli of diabetic nephropathy. Fibrogenic cytokines, particularly transforming growth factor (TGF)-beta1, play a central role in progressive renal fibrosis. Activated TGF-beta1 is known to increase the production of ECM as collagen and fibronectin. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an inbred strain that spontaneously develops non-insulin-dependent diabets mellitus which progresses to diabetic glomerulosclerosis. This study is examined the time points and localization of TGF-beta1 in diabetic glomerulosclerosis of OLETF rats. METHODS: OLETF rats, a chronic model for human type 2 diabetes mellitus, and age-matched control (LETO) rats were used. Blood was assayed for glouse and body weight were measured. From rats aged 30 to 60 weeks, animals were sacrificed under ether anesthesia, and both kidneys were removed. Portions of these tissues were processed for light microscopy and immunohistochemistry of TGF-beta1. TGF-beta1 mRNA levels were measured by reverse transcription polymerase chain reaction. RESULTS: The body weights of OLETF rats were significantly greater than those of LETO rats from the age of 30 to 40 weeks, but those of OLETF rats gradually decreased after 40 weeks of age. There were no differences in body weights between these two strains at 50 weeks of age. Blood glucose levels of OLETF rats increased significantly with aging and were significantly higher than those of LETO rats after 32 weeks of age. There was no significant fibrosis in kidney of OLETF and LETO rats at all ages examined. The TGF-beta1 protein was detected in the glomerular endothelial cells and tubular epithelial cells of OLETF rats at 35 to 38 weeks of age. The TGF-beta1 protein in tubular epithelial cells of OLETF rats was strongly expressed at 60 weeks of age, whereas the glomerular endothelial cells scarcely detected the expression of TGF-beta1 protein. In LETO rat kidneys, the TGF-beta1 protein is detected in the glomerular endothelial cells at 35 weeks of ages, but is not detected in any other cells. The TGF-beta1 mRNA of OLETF rats were increased at 32 weeks of age, higher than that of control LETO rats. CONCLUSION: Until 60 weeks of age, glomerular sclerosis became very weakly in OLETF rats. However, in 30-week-old OLETF rats, the blood gloucose levels and TGF-beta1 protein increased significantly. The TGF-beta1 protein was detected in the glomerular endothelial cells and tubular epithelial cells of OLETF rats at 37 weeks of age.