Interactions of orexins/hypocretins with adrenocortical functions

The neuropeptides orexin A and B (hypocretin-1 and -2) are involved in numerous central regulation processes such as energy homeostasis, sleeping behaviour and addiction. The expression of orexins and orexin receptors in a variety of tissues outside the brain and the presence of orexin A in the circulation indicate the existence of an additional peripheral orexin system. Furthermore, it is well established that orexins exert an influence on the regulation of the hypothalamus-pituitary-adrenal axis, acting both on its central and peripheral branch. In rat and human adrenal cortices the expression of both orexin receptors has been verified with a predominance of OX(2)R. The local expression of orexin receptors was observed to be gender specific and to be modified by plasma glucose and insulin concentrations, nutritional status as well as gonadal steroids. Various studies consistently demonstrated orexin A to enhance glucocorticoid secretion of rat and human adrenal cortices, while orexin B was found to be either less potent or ineffective. On the contrary, the influence of orexins on adrenocortical aldosterone production and cell proliferation is still more controversial. Recent findings indicate that orexins stimulate adrenocortical steroidogenesis by augmenting transcription of selective steroidogenic enzymes and proteins such as steroidogenic acute regulatory protein. Both, G(q) and G(s), signalling pathways with a downstream activation of MAP kinases appear to be involved in this regulation.