Angiotensin II (Ang II) and adrenocorticotropic hormone stimulate aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex through induction of the expression of the steroidogenic acute regulatory (StAR) protein, which promotes intramitochondrial cholesterol transfer. To understand the mechanism of this induction of the StAR protein, we have examined the effect of Ang II and forskolin, a mimicker of adrenocorticotropic hormone action, on two transcription factors known to modulate StAR gene expression in opposite ways, DAX-1 and SF-1, in bovine adrenal glomerulosa cells in primary culture. Ang II markedly inhibited DAX-1 protein expression in a time-and concentrationdependent manner (to 38.7 ؎ 12.9% of controls at 3 nM after 6 h, p < 0.01), an effect that required de novo protein synthesis and ERK2/1 activation. This effect was associated with a concomitant decrease in DAX-1 mRNA and an increase in mitochondrial StAR protein levels. Similarly, forskolin dramatically repressed DAX-1 protein and mRNA expression (to 19.6 ؎ 1.8 and 50.3 ؎ 4.7% of controls, respectively, p < 0.01). Neither Ang II nor forskolin affected DAX-1 protein and mRNA stability. The aldosterone response to Ang II was markedly reduced (to 59 ؎ 4% of controls, p < 0.01) in transiently transfected cells overexpressing DAX-1. Whereas Ang II was without effect on SF-1 expression, forskolin significantly increased SF-1 protein and mRNA levels in a cycloheximide-sensitive manner (to 167.4 ؎ 16.6 and 173.1 ؎ 25.1% of controls after 6 h, respectively, p < 0.01). These results demonstrate that the balance between repressor and inducer function of DAX-1 and SF-1 are of critical importance in the regulation of adrenal aldosterone biosynthesis.
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 L-, and beta 2-adrenoceptor agonists BRL 37344, dobutamine, and terbutaline inhibited ob gene expression in mouse brown adipocytes differentiated in culture with EC50 values of 0.3, 1.0, and 85 nM, respectively. Leptin secretion by the cells under basal conditions was 78 +/- 10 pg/microgram 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)2cAMP (10-100 microM) and forskolin (20 microM) mimicked the effect of the beta-adrenoceptor agonists. FFA (150-800 microM) 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 in inhibited when the sympathetic nervous system is stimulated.
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