The tissue distribution of the human b b 3 -adrenoceptor studied using a monoclonal antibody: Direct evidence of the b b 3 -adrenoceptor in human adipose tissue, atrium and skeletal muscle 2,3 The human b 3 -adrenoceptor was later cloned by Emorine et al. 4 The pharmacology of the cloned b 3 -adrenoceptor agreed with the pharmacological data previously obtained in rodent adipose tissue, gut, and skeletal muscle in that the badrenoceptors in these tissues were insensitive to classical b-adrenoceptor antagonists such as propranolol.5 ± 8 Aryloxypropanolamine b 1 ab 2 adrenoceptor antagonists, exempli®ed by CGP12177, evoke a lipolytic response in rat adipose tissue through agonism at b 3 -adrenoceptors. 9 Similarly, selective b 3 -adrenoceptor agonists, such as BRL-37344, showed similar or greater potency than isoproterenol in stimulating lipolysis, but were much less potent than isoproterenol in stimulating responses mediated by b 1 -or b 2 -adrenoceptors. 10 The assessment of the pharmacological role of b 3 -adrenoceptors in human tissues has proved more controversial. For example, lipolysis in human white adipocytes induced by isoproterenol is sensitive to propranolol.11 Also, CGP12177-induced lipolytic responses have been demonstrated by some 12 ± 14 but not others. 9,15 It is now evident from comparisons of cloned human and rat b 3 -adrenoceptors that there are signi®cant species differences in pharmacology. 16 Attempts to detect b 3 -mRNA in human tissues using reverse-transcription PCR have also given conicting results. Krief et al 17 detected b 3 -adrenoceptor mRNA in several tissues, including gall bladder, adipose tissue and colon, while Thomas and Liggett 18 failed to detect a b 3 -adrenoceptor signal. Recently, RNAase protection assays, that do not rely on ampli®cation techniques, were used to identify b 3 -adrenoceptor mRNA in a variety of human tissues, including

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 mgakg), LG 100324 (20 mgakg), BRL 49653 (3 mgakg) 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 signi®cantly lowered blood glucose concentrations after 1 week of treatment. The 5 h fasted plasma insulin concentration was signi®cantly 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 signi®cant differences in the rate of hepatic glucose output and whole body glucose disposal, except that, in experiment 1, BRL 49653 caused signi®cant 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 rats received a similar insulin infusion concentration. This suggests that both the rexinoids and BRL 49653 increased insulin clearance. CONCLUSIONS: Chronic administration of retinoid X receptor agonists LG 100268 and LG 100324 to Zucker faafa rats reduces food intake and body weight gain, lowers plasma insulin concentrations while maintaining normoglycaemia, indicating an improvement of insulin sensitivity.