EFFECTS OF BETA-ADRENOCEPTOR SUBTYPE STIMULATION ON OBESE GENE MESSENGER-RIBONUCLEIC-ACID AND ON LEPTIN SECRETION IN MOUSE BROWN ADIPOCYTESDIFFERENTIATED IN CULTURE

The ob gene product is known to control food intake and energy expendi ture. 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 st udied in mouse brown adipocytes differentiated in culture. These cells highly expressed the beta(3)-adrenoceptor, the uncoupling protein, an d the ob gene mRNAs. The ob gene was expressed in mouse brown adipocyt es earlier than in mouse white adipocytes under the same culture condi tions and to a similar level. The beta(3)-, beta(1)-, and beta(2)-adre noceptor agonists BRL 37344, dobutamine, and terbutaline inhibited ob gene expression in mouse brown adipocytes differentiated in culture wi th EC(50) values of 0.3, 1.0, and 85 nM, respectively. Leptin secretio n 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 o b 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 m ight 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-adrenocept or agonists. FFA (150-800 mu M) had only a small inhibitory effect on ob gene mRNA expression. The results suggest the existence in brown ad ipose tissue of a retroregulatory pathway by which leptin production i s inhibited when the sympathetic nervous system is stimulated.