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

Glucocorticoids may inhibit brown adipose tissue (BAT) thermogenesis acting at a central level as well as reducing the responses of the tissue to adre nergic stimulation in vivo. This latter effect is not well understood. We i nvestigated whether or not glucocorticoids directly seduce the expression o f 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 st imulation in these cells is qualitatively and quantitatively similar to tha t seen in vivo. Dexamethasone and other glucocorticoids, given simultaneous ly with NE, nearly abolish the ensuing UCP1 mRNA accumulation. This effect was negated by the glucocorticoid receptor antagonist RU-486. Significant i nhibition is seen within the physiological range of concentrations, with ID (50)s for dexamethasone and corticosterone of 1 and 75 nM, respectively. Wi thin the time span of the experiments, glucocorticoids did not reduce the s trength of the NE signal nor did they necessitate ongoing protein synthesis or reduce the stability of mature UCP1 mRNA, but they significantly inhibi ted the stimulation of transcription by NE ina run-on in vitro transcriptio n assay, These observations indicate that glucocorticoids are powerful inhi bitors of the UCP1 gene response to adrenergic stimulation acting at transc riptional level, and provide further evidence for a global inhibitory effec t of glucocorticoids on BAT thermogenesis. (C) 2000 Elsevier Science Irelan d Ltd. All rights reserved.