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.
Centre for Study and Research on Obesity, Department of Pharmacology, School of Medicine, Ospedale L. Sacco, Milan University, Italy.
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D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers; D007473:Ion Channels; D020738:Leptin; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins; D011412:Propanolamines / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D022702:Receptors, Adrenergic, beta-3; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071256:Uncoupling Protein 1
C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D017931:DNA Primers; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011412:Propanolamines; D011506:Proteins; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1