Retinoid X receptor agonists have anti-obesity effects and improve insulinsensitivity in Zucker fa/fa rats

OBJECTIVE: To investigate whether retinoid X receptor agonists act as insul in 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 onc e 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-hyperi nsulinaemic clamp) and tissue glucose utilization. RESULTS: The retinoid X receptor agonists (rexinoids) LG 100268 and LG 1003 24 caused a reduction in the food intake of obese Zucker rats relative to c ontrols 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 tr eated with BRL 49653 tended to increase. Both rexinoids and BRL 49653 reduc ed the plasma insulin concentration of fed rats. LG 100268 and LG 100324 al so significantly lowered blood glucose concentrations after 1 week of treat ment. The 5 h fasted plasma insulin concentration was significantly lower i n 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 affec ted by any of the treatments. Under euglycaemic-hyperinsulinaemic clamp con ditions, there were no significant differences in the rate of hepatic gluco se output and whole body glucose disposal, except that, in experiment 1, BR L 49653 caused significant increase in the glucose infusion rate and muscle glucose utilization. In experiment 2, a similar glucose infusion rate to t he controls was achieved in all treatment groups but the steady-state insul in concentration in the treated animals was only about 50% of that in the c ontrol animals, despite the fact that all rats received a similar insulin i nfusion concentration. This suggests that both the rexinoids and BRL 49653 increased insulin clearance. CONCLUSIONS: Chronic administration of retinoid X receptor agonists LG 1002 68 and LG 100324 to Zucker fa/fa rats reduces food intake and body weight g ain, lowers plasma insulin concentrations while maintaining normoglycaemia, indicating an improvement of insulin sensitivity.