SR59230A BLOCKS BETA(3)-ADRENOCEPTOR-LINKED MODULATION OF UNCOUPLING PROTEIN-1 AND LEPTIN IN RAT BROWN ADIPOCYTES

Experimental evidence suggests that, by stimulating energy expenditure in brown fat, selective beta(3)-adrenoceptor agonists can reduce body weight in obese rodents. In order to investigate further the physiolo gical role of beta(3)-adrenoceptors in brown adipocytes, we analysed t he effects of selective beta(3)-adrenoceptor agonists and antagonists on uncoupling protein-1 and leptin gene expression in culture-differen tiated brown fat cells. Our main findings were that: (i) the leptin ge ne is expressed in brown adipocytes; (ii) the selective beta(3)-adreno ceptor agonist, -2-yl]-(2R)-2-hydroxy-2-(3-chlorophenil)ethanamine hyd rochloride (SR58611A), inhibits leptin gene while inducing uncoupling protein-1 gene expression; (iii) these opposite effects of SR58611A ar e antagonized by the selective beta(3)-adrenoceptor antagonist, SS-ena ntiomer 2,3,4-tetrahydronaphth-1-ylaminol]-(2S)-2-propanol oxalate (SR 59230A), but not by the selective beta(1)-adrenoceptor antagonist -met hyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP20712A); a nd (iv) these effects are due to increased cyclic AMP levels. These re sults confirm by means of a different experimental approach that beta( 3)-adrenoceptors play a central role in controlling the expression of genes that are important for brown fat function. (C) 1998 Elsevier Sci ence B.V. All rights reserved.