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Review Article

Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis

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

I. Introduction

II. Biology of Orexins and Their Receptors

A. Orexin Biosynthesis

B. Orexin Receptors and Their Signaling Mechanisms

III. Expression and Function of Orexins and Their Receptors in the Central Branch of the Hypothalamic-Pituitary-Adrenal Axis

A. Expression of Orexins and Their Receptors

1. Hypothalamus.

a. Orexin expression.

b. Orexin receptor expression.

2. Pituitary Gland.

B. Effects of Orexins

IV. Expression and Function of Orexins and Their Receptors in the Peripheral Branch of the Hypothalamic-Pituitary-Adrenal Axis

A. Expression of Orexins and Their Receptors

1. Orexin Expression.

2. Orexin Receptor Expression

a. Human adrenal gland.

b. Rat adrenal gland.

c. Sheep and pig adrenal gland.

B. Effects of Orexins

1. Aldosterone Secretion.

2. Glucocorticoid Secretion.

a. Indirect mechanism.

b. Direct mechanism.

3. Adrenocortical Cell Growth.

4. Catecholamine Secretion.

V. Involvement of Orexins in the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis

A. Stressful Conditions

B. Adrenocortical Tumors

1. Orexin and Orexin Receptor Expression.

2. Effects of Orexins on Secretion and Growth.

3. Conclusions.

C. Pheochromocytomas

1. Orexin and Orexin Receptor Expression.

2. Effects of Orexins on Catecholamine Secretion.

VI. Concluding Remarks

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.

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