Orexins, or hypocretins, are peptides originally found in the hypothalamus, and have been shownto be involved in the stabilization and maintenance of sleep and wakefulness. In addition, thesepeptides are known for their actions on energy homeostasis by increased heat production orphysical activity. Previous results suggest them to be also involved in peripheral actions on theregulation of intestinal secretion, depending on the subject’s nutritional status (fasted-fed).Orexin-A and Orexin-B peptides, are derived from the prepro-orexin precursor protein. Theseligands bind to two G-protein-coupled receptors, orexin-1 and -2 -receptors. Despite intensiveresearch, the role of orexins has not yet been clarified. The aim of the present study was toinvestigate the role of orexins and their receptors on sleep and wake patterns, energy homeostasisand intestinal secretion.
The effects of orexins on sleep and wakefulness, and energy homeostasis were studied in anovel transgenic mouse line, overexpressing the human prepro-orexin gene. The overexpressionof prepro-orexin and orexin-A was confirmed in the hypothalami of transgenic mice. Thetransgenic mice showed a significant reduction in their REM sleep during day and night time, anddifferences in their vigilance states in the light/dark transition periods. In addition, the micedemonstrated a significantly elevated day time food intake at room temperature, and an increasedmetabolic heat production independent of uncoupling protein 1 mediated thermogenesis in brownadipose tissue. Instead, transgenic mice showed increased levels of uncoupling protein 2 in whiteadipose tissue. Furthermore, transgenic mice significantly decreased their total locomotor activityduring the first two nights in response to cold exposure (+4°C).
The effect of orexins and their receptors on duodenal HCO3¯ secretion were studied after anovernight (16 h) food deprivation in an in situ perfused organ. Fasting decreased the expression oforexin receptors in rat duodenal mucosa and in acutely isolated duodenal enterocytes.Furthermore, food deprivation abolished OXA induced duodenal mucosal HCO3¯ secretion inrats, and intracellular calcium signalling in isolated rat and human duodenal enterocytes.
In conclusion, the present thesis demonstrates that orexins inhibit REM sleep. In addition,peptides affect increasingly on metabolic heat production, independent of uncoupling protein 1mediated thermogenesis. Furthermore, the orexin system has a significant role in duodenalbicarbonate secretion, which is regulated by the presence of food in the intestine.
