The presence of nerve growth factor (NGF) and the ability of adrenergic stimulation to affect the rate of its synthesis in mouse, rat, and human brown adipose tissue (BAT) were investigated. Addition of conditioned medium, obtained from preconfluent and confluent brown adipocytes, to PC12 cells induced typical morphological changes similar to those due to NGF itself. Anti-NGF antibodies blocked this action. Moreover, NGF mRNA was detected by RT-PCR both in BAT and in brown adipocyte preparations. That NGF is synthesized in and released from brown fat cells was confirmed by immunoblotting. When the animals were exposed to low temperatures, NGF production declined. The effect of cold exposure could be mimicked by the addition of norepinephrine (NE) at day 4 or 8 (preconfluent and confluent cells, respectively). NE depletion obtained by reserpine injection induced a drastic increase of BAT NGF production. In both rat and human BAT, immunohistochemistry identified distinct anatomical structures that express the low affinity neurotropin receptor, termed p75NGFR. BAT production of NGF was higher in genetically obese rats and mice than in their lean counterparts, a difference that becomes more evident with age. Prolonged exposure to low temperature significantly decreased the BAT NGF synthesis also in obese animals. We conclude that NGF is synthesized in and released from brown fat cells, its production being inversely dependent on sympathetic activity, in both physiological and pathophysiological conditions, and increased in genetic animal models of obesity.