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The effect of short-term bezafibrate (BF) administration over time on the expression of UCP mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into a high-dose (100 mg/kg) BF group (n = 15), a low-dose (10 mg/kg) BF group (n = 15) and a control group (n = 15), and followed for 14 days. Feed intake by the high-dose BF group increased significantly between days 10 and 14 of administration. Triglyceride, free fatty acid, and T(4) levels decreased significantly in a dose-dependent manner in the high-dose BF group. Leptin and insulin levels significantly decreased on days 3 and 7. Throughout the study period, liver UCP2 mRNA increased in the high-dose BF group. On day 3 of BF administration, the levels of UCP2 mRNA expression in the skeletal muscles as well as UCP3 mRNA expression in the WAT were significantly increased in the high-dose BF group. PPAR-alpha mRNA significantly increased in the liver on day 3 of BF administration. We thus conclude that the PPAR-alpha-mediated effects of BF on the expression of liver UCP2 may be one of the factors that helped to decrease insulin levels.

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The effect of short-term bezafibrate (BF) administration over time on the expression of adiponectin mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into the high-dose (100 mg/kg) BF group (n=15), the low-dose (10 mg/kg) BF group (n=15), or the control group (n=15) and followed up for 14 d. Tri-glyceride and free fatty acid levels significantly decreased in a dose-dependent manner in the high-dose BF group. The insulin levels increased with time, although they were significantly lower in the high-dose BF group on d 3 and 7 than the control group. Adiponectin levels significantly increased in the high-dose BF group. On d 14 of BF administration, the levels of VLDL and chy-lomicron were significantly lower in BF groups, and adiponectin mRNA expression in the white adipose tissue was significantly higher in the high-dose BF group. Findings from this study suggest that in type 2 diabetes with insulin resistance, hypertriglyceridemia is closely linked to adiponectin.

Introduction. The effect of beta3-adrenergic receptor agonists on beta cells in the islets of Langerhans is not yet clear. This study examined the beta3-adrenergic receptor agonist on beta cells in the islets of Langerhans. Methods. Obese diabetic C57BL/KsJ-db/db mice were treated with KTO-7924, a newly-developed beta3-adrenergic receptor agonist for 28-day. We analyzed plasma parameters, insulin resistance, and insulin-positive areas among beta-cells in the islets of Langerhans. Results and Conclusion. After a 28-day oral administration period, plasma levels of hemoglobin (Hb) A1c, glucose, triglyceride (TG), and free fatty acid (FFA) were all significantly reduced in KTO-7924 treatment groups compared with controls. Plasma adiponectin levels decreased with age in the control group, but were significantly higher in a treatment group throughout the study period. Furthermore, sequential administration of KTO-7924 led to an improvement in insulin resistance in the OGTT (Oral glucose tolerance test (OGTT)), and an increase in the percentage of insulin-positive areas among beta-cells in the islets of Langerhans compared with controls. This is the first study to show islet histology after treatment of a beta3-adrenergic receptor agonist, and reveals that KTO-7924 reduces hyperglycemia, and protects beta-cells in the islets of Langerhans of db/db mice.

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.