Orexins are peptides well known for their actions on arousal but also on energy homeostasis. Recent data have suggested a role for orexins in brown adipose tissue (BAT) mediated thermogenesis. An injection of orexin-A (OXA) increases the metabolic rate in mice, while prepro-orexin knock-out mice under a high fat diet show lowered metabolic rate with reduced uncoupling protein 1 (UCP1) levels in BAT. Even though these mice also show decreased physical activity, the observed obese phenotype is likely due to impaired BAT thermogenesis. Transgenic (tg) mice line expressing human prepro-orexin (hPPO) under its own promoter was used in order to investigate the effects of orexins on energy homeostasis. We used real-time PCR to analyse gene expression levels of UCPs 1- 3 from BAT, white adipose tissue (WAT) and skeletal muscle. Metabolic performance, total locomotor activity as well as drinking and feeding behavior of mice housed at +21 ordm;C or +4ordm;C were measured using an automated monitoring system. The hPPO/OXA was expressed in hypothalamus of tg mice. Tg mice gain less weight than wt mice. At room temperature tg mice fed with normal low fat chow showed increased heat production with no change on total food or drink consumption, or locomotor activity. Interestingly, we did not see any significant difference in BAT UCP1 levels between genotypes. In cold, tg mice decreased significantly their locomotor activity compared with wt mice during the first two nights. In addition to recently proposed actions of orexins on BAT mediated thermogenesis our results demonstrate an thermogenic effect independent of UCP1 and BAT. Supported in part by the Academy of Finland.