SR59230A blocks beta3-adrenoceptor-linked modulation of upcoupling protein-1 and leptin in rat brown adipocytes.

Experimental evidence suggests that, by stimulating energy expenditure in brown fat, selective beta3-adrenoceptor agonists can reduce body weight in obese rodents. In order to investigate further the physiological role of beta3-adrenoceptors in brown adipocytes, we analysed the effects of selective beta3-adrenoceptor agonists and antagonists on uncoupling protein-1 and leptin gene expression in culture-differentiated brown fat cells. Our main findings were that: (i) the leptin gene is expressed in brown adipocytes; (ii) the selective beta3-adrenoceptor agonist, N[(2S)-7-carbethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy- 2-(3-chlorophenil)ethanamine hydrochloride (SR58611A), inhibits leptin gene while inducing uncoupling protein-1 gene expression; (iii) these opposite effects of SR58611A are antagonized by the selective beta3-adrenoceptor antagonist, SS-enantiomer 3-(2-ethylphenoxy)-1-(1S),2,3,4-tetrahydronaphth-1-ylamin ol]-(2S)-2-propanol oxalate (SR59230A), but not by the selective beta1-adrenoceptor antagonist (+/-)-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4(1-methyl- 4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP20712A); and (iv) these effects are due to increased cyclic AMP levels. These results confirm by means of a different experimental approach that beta3-adrenoceptors play a central role in controlling the expression of genes that are important for brown fat function.