Norepinephrine but not hypoxia stimulates HIF-1α gene expression in brown adipocytes

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