Cross-talk between orexins (hypocretins) and the neuroendocrine axes (hypothalamic–pituitary axes)

Lesioning and electrical stimulation experiments carried out during the first half of the twentieth century showed that the lateral hypothalamic area (LHA) is involved in the neuroendocrine control of hormone secretion. However, the molecular basis of this phenomenon remained unclear until fifty years later when in 1998, two different laboratories discovered a new family of hypothalamic neuropeptides, the orexins or hypocretins (OX-A/Hcrt1 and OX-B/Hcrt2). Since then, remarkable evidence has revealed that orexins/hypocretins play a prominent role in regulating virtually all the neuroendocrine axes, acting as pivotal signals in the coordination of endocrine responses with regards to sleep, arousal and energy homeostasis. The clinical relevance of these actions is supported by human data showing impairment of virtually all the neuroendocrine axes in orexin/hypocretin-deficient narcoleptic patients. Here, we summarize more than ten years of knowledge about the orexins/hypocretins with particular focus on their role as neuroendocrine regulators. Understanding this aspect of orexin/hypocretin physiology could open new therapeutic possibilities in the treatment of sleep, energy homeostasis and endocrine pathologies.