Glucocorticoids inhibit the transcriptional response of the uncoupling protein-1 gene to adrenergic stimulation in a brown adipose cell line

Abstract

Glucocorticoids may inhibit brown adipose tissue (BAT) thermogenesis acting at a central level as well as reducing the responses of the tissue to adrenergic stimulation in vivo. This latter effect is not well understood. We investigated whether or not glucocorticoids directly reduce the expression of the key molecule for BAT thermogenesis, uncoupling protein-1 (UCP1), and if so, to what extent and by what mechanisms. We used HIB-1B brown adipose cells obtained from a hibernoma. The response of UCP1 mRNA to adrenergic stimulation in these cells is qualitatively and quantitatively similar to that seen in vivo. Dexamethasone and other glucocorticoids, given simultaneously with NE, nearly abolish the ensuing UCP1 mRNA accumulation. This effect was negated by the glucocorticoid receptor antagonist RU-486. Significant inhibition is seen within the physiological range of concentrations, with ID(50)s for dexamethasone and corticosterone of 1 and 75 nM, respectively. Within the time span of the experiments, glucocorticoids did not reduce the strength of the NE signal nor did they necessitate ongoing protein synthesis or reduce the stability of mature UCP1 mRNA, but they significantly inhibited the stimulation of transcription by NE in a run-on in vitro transcription assay. These observations indicate that glucocorticoids are powerful inhibitors of the UCP1 gene response to adrenergic stimulation acting at transcriptional level, and provide further evidence for a global inhibitory effect of glucocorticoids on BAT thermogenesis.