Effects of beta-adrenoceptor subtype stimulation on obese gene messenger ribonucleic acid and on leptin secretion in mouse brown adipocytes differentiated in culture

The ob gene product is known to control food intake and energy expenditure. To determine whether thermogenic agents directly control ob gene expression, the effects of beta-adrenoceptor agonists on the level of the ob gene messenger RNA (mRNA) and on leptin secretion have been studied in mouse brown adipocytes differentiated in culture. These cells highly expressed the beta(3)-adrenoceptor, the uncoupling protein, and the ob gene mRNAs. The ob gene was expressed in mouse brown adipocytes earlier than in mouse white adipocytes under the same culture conditions and to a similar level. The beta(3)-, beta(1)-, and beta(2)-adrenoceptor agonists BRL 37344, dobutamine, and terbutaline inhibited ob gene expression in mouse brown adipocytes differentiated in culture with EC(50) values of 0.3, 1.0, and 85 nM, respectively. Leptin secretion by the cells under basal conditions was 78 +/- 10 pg/mu g DNA . 4 h and was decreased by exposure to the beta-adrenoceptor agonists. The ob gene mRNA half-life was 9.4 h and was decreased to 2.4 h by 1 nM BRL 37344, indicating that the inhibitory effect of the beta(3)-agonist might be due to destabilization of ob gene mRNA. (Bu)(2)cAMP (10-100 mu M) and forskolin (20 mu M) mimicked the effect of the beta-adrenoceptor agonists. FFA (150-800 mu M) had only a small inhibitory effect on ob gene mRNA expression. The results suggest the existence in brown adipose tissue of a retroregulatory pathway by which leptin production is inhibited when the sympathetic nervous system is stimulated.