Orexins were isolated from the hypothalamus and shown to be involved in feeding, energy homeostasis and vigilance. Orexins have also been described to act outside the CNS in the periphery. Recently, orexin-A has been reported to affect thermogenesis. Since the peripheral actions of orexins are still very much unclear, we developed a transgenic mouse line overexpressing the human prepro-orexin (hPPO) gene under the control of endogenous promoter. The mouse line was produced using standard techniques. Transgenic (tg) mice were characterized using Southern and Western blotting. Feeding and drinking behavior, locomotor activity and metabolic performance of 6 tg and 6 syngenic (sg) mice were tested using an automated monitoring system. Total RNA was extracted from white and brown adipose tissue (WAT and BAT) and skeletal muscle from fed mice and reverse transcribed to cDNA. Gene expression analysis of uncoupling proteins (UCP) 1, 2 and 3 was performed by quantitative real-time PCR. Tg animals appear to have normal breeding behaviour and body weight. Our transgenic animals showed significantly increased expression of hPPO. Preliminary evaluation documented a similar food / drink intake and locomotor activity in tg and sg littermates. However, we found a significant effect on heat production in tg animals. Expression levels of UCP2 in WAT were significantly increased in tg mice compared to their sg littermates, while the expression of UCP1 and UCP3 did not significantly differ. The increase in expression of UCP2 in WAT correlated to an increased heat production. In addition, as orexins have been described as orexigenic peptides they also affect body homeostasis via heat production.

Supported by the Academy of Finland and the Novo Nordisk Foundation.