Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis
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Raffaella Spinazzi, Paola G. Andreis, Gi
Hypothalamic-Pituitary-Adrenal,,OrexinsintheRegulationoftheHypothalamic-Pituitary-AdrenalAxis
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Departments of Human Anatomy and Physiology (R.S., P.G.A., G.G.N.) and Clinical and Experimental Medicine (G.P.R.), School of Medicine, University of Padua, Padua, Italy
Abstract
Orexin-A and orexin-B are hypothalamic peptides that act via two G protein-coupled receptors, named orexin type 1 and type 2 receptors (OX1-Rs and OX2-Rs). The most studied biological functions of orexins are the central control of feeding and sleep, but in the past few years findings that orexin system modulates the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches, have accumulated. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and median eminence and orexin receptors in pituitary corticotropes, adrenal cortex, and medulla. Whereas the effects of orexins on adrenal aldosterone secretion are doubtful, compelling evidence indicates that these peptides enhance glucocorticoid production in rats and humans. This effect involves a 2-fold mechanism: 1) stimulation of the adrenocorticotropin-releasing hormone-mediated pituitary release of adrenocorticotropin, which in turn raises adrenal glucocorticoid secretion; and 2) direct stimulation of adrenocortical cells via OX1-Rs coupled to the adenylate cyclase-dependent cascade. The effects of orexins on catecholamine release from adrenal medulla are unclear and probably of minor relevance, but there are indications that orexins can stimulate in vitro secretion of human pheochromocytoma cells via OX2-Rs coupled to the phospholipase C-dependent cascade. Evidence is also available that orexins enhance the growth in vitro of adrenocortical cells, mainly acting via OX2-Rs. Moreover, findings suggest that the orexin system may favor HPA axis responses to stresses and play a role in the pathophysiology of cortisol-secreting adrenal adenomas.
I. Introduction
Orexins A and B are neuropeptides that were isolated from the rat hypothalamus by two independent groups of investigators in 1998 (De Lecea et al., 1998; Sakurai et al., 1998). They were originally named hypocretins because of their hypothalamic localization and their supposed similarity to secretin. Thereafter, their names was changed to orexins on the basis of their predominant expression in the hypothalamic feeding centers and their involvement in the control of food intake. Simultaneously with the discovery of orexins, two G protein-coupled receptors for these endogenous ligands have been identified by the same groups of investigators and called orexin type 1 and type 2 receptors (OX1-Rs1 and OX2-Rs). Subsequent investigations showed that the orexin system also plays a role in the regulation of sleep/wakefulness, because orexin gene knockout mice and dogs with nonfunctional OX2-Rs because of a gene mutation display a narcolepsy-like condition (Chemelli et al., 1999; Lin et al., 1999), and narcoleptic humans lack orexin-containing neurons in the hypothalamus and orexins in the cerebrospinal fluid (Nishino et al ......
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