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Aims/hypothesis: The 11β-hydroxysteroid dehydrogenase type-1 inhibitor BVT.2733 lowers blood glucose and insulin in mutant mouse models of obesity and diabetes. Its effects on energy balance and body composition, and their contribution to improved glucose homeostasis have received little attention. Materials and methods: BVT.2733 (100 mg/kg, orally) was given twice daily to lean and diet-induced obese mice for 16 or 17 days. A group of obese mice was pair-fed to the amounts consumed by BVT.2733-treated mice. Results: In both obese and lean mice, BVT.2733 reduced food intake and weight gain, but increased water intake. Pair-feeding caused almost as great a decrease in body weight as BVT.2733. Energy expenditure was 38±8% higher in the BVT.2733-treated obese mice than in the pair-fed mice. Terminal plasma corticosterone was raised, lean body weight reduced and percentage fat unchanged in the pair-fed mice (control, 47.8±2.6%; pair-fed, 47.1±1.9%), whereas BVT.2733 did not reduce lean mass, but did reduce percentage fat (40.9±2.0%). BVT.2733 but not pair-feeding reduced both the glucose tolerance AUC and the plasma insulin concentration 30 min after giving glucose. Conclusions/interpretation: BVT.2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate whether retinoid X receptor agonists act as insulin sensitizers and compare their effects with that of thiazolidinedione BRL 49653 in obese Zucker rats. DESIGN: In two independent studies, obese Zucker rats were dosed orally once daily for 14 days with one of the following treatments: LG 100268 (20 mg/kg), LG 100324 (20 mg/kg), BRL 49653 (3 mg/kg) or vehicle. MEASUREMENTS: Daily food intake and body weight gain, blood glucose, plasma and pancreatic insulin, whole body glucose disposal (by euglycaemic–hyperinsulinaemic clamp) and tissue glucose utilization. RESULTS: The retinoid X receptor agonists (rexinoids) LG 100268 and LG 100324 caused a reduction in the food intake of obese Zucker rats relative to controls and to rats receiving BRL 49653. The two rexinoids also produced a marked decrease in the body weight gain, whereas the growth rate of rats treated with BRL 49653 tended to increase. Both rexinoids and BRL 49653 reduced the plasma insulin concentration of fed rats. LG 100268 and LG 100324 also significantly lowered blood glucose concentrations after 1 week of treatment. The 5 h fasted plasma insulin concentration was significantly lower in the rexinoid-treated groups and the terminal insulin level (at the end of the clamp) tended to be lower in all treated groups compared with animals given the dosing vehicle. However, pancreatic insulin content was not affected by any of the treatments. Under euglycaemic–hyperinsulinaemic clamp conditions, there were no significant differences in the rate of hepatic glucose output and whole body glucose disposal, except that, in experiment 1, BRL 49653 caused significant increase in the glucose infusion rate and muscle glucose utilization. In experiment 2, a similar glucose infusion rate to the controls was achieved in all treatment groups but the steady-state insulin concentration in the treated animals was only about 50% of that in the control animals, despite the fact that all... [ABSTRACT FROM AUTHOR]