The cellular response to hypoxic stress is mainly mediated via activation of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha). In the present study, the sympathetically controlled brown adipose tissue was used to investigate the effect of norepinephrine on HIF-1 alpha gene expression. Norepinephrine increased HIF-1 alpha mRNA levels in cultured brown adipocytes, whereas the hypoxia-mimic cobalt was without effect. Cold exposure of mice increased HIF-1 alpha gene expression in brown adipose tissue. In UCP1-ablated mice, which are incapable of inducing thermogenic oxygen consumption in brown adipose tissue, cold exposure generated a significantly higher elevation of HIF-1 alpha mRNA levels than in wild-type. These results demonstrate that cold-induced HIF-1 alpha gene expression is independent of thermogenic oxygen consumption leading to hypoxia, but is consistent with a norepinephrine regulation of HIF-1 alpha gene expression. Thus, by elevating HIF-1 alpha gene expression, norepinephrine may mediate an increased potential to respond to hypoxia in brown adipose tissue and possibly in other tissues. (c) 2005 Elsevier Inc. All rights reserved.