The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function

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Abstract

The hypocretins/orexins are hypothalamic peptides most recognized for their significant effects on feeding and arousal. Indeed, loss of the peptides results in a cataplexy quite similar to that observed canine models of human narcolepsy. However, neurons producing these peptides project to numerous brain sites known to be important in neuroendocrine regulation of pituitary function and autonomic centers as well. Results from numerous laboratories have suggested broad physiological roles for the hypocretins/orexins in neuroendocrine and autonomic regulation as a consequence of actions in the dorsal vagal complex, paraventricular nucleus, and pituitary. This review focuses upon evidence for potential physiologic roles for the peptides in these sites.

Introduction

Since the initial description of the hypocretins/orexins (Hcrt/ORX) in 1998, there has been a tremendous concerted effort to better understand the apparently diverse physiological roles of these novel peptides as outlined in a number of recent reviews [16], [19], [43], [46], [64], [66], [81]. In this review, we will first outline studies describing the existence and central distribution of these peptides, as well as the control of Hcrt/ORX producing neurons. We will then focus on subsequent work suggesting broad physiological roles for the Hcrt/ORX in neuroendocrine and autonomic regulation, and within this context will specifically review the current literature suggesting specific roles of these peptides in the dorsal vagal complex, paraventricular nucleus, and pituitary.

Section snippets

Discovery and central distribution

From a rat cDNA library enhanced for hypothalamic-specific clones, Gautvik and colleagues [24] identified the potential expression of a novel peptide in the posterior/lateral hypothalamus. Two years later, these same investigators [15] identified the prohormone encoded from this novel mRNA and predicted that posttranslational modification resulted in the formation to two peptides, both containing C-terminal glycine residues, suggesting that these peptides were C-terminally amidated. Since these

Orexinergic neurons

Perhaps the most striking feature of the ORX literature is the established description of the lateral hypothalamic/perifornical region as the primary location of Hcrt/ORX producing neurons [4], [15], [18], [32], [57], [60], [65]. This observation leads to the conclusion that the extensive CNS distribution of orexinergic fibers represents the efferent projections of this unique group of neurons. In turn, such observations make it immediately apparent that understanding the factors controlling

Neuroendocrine and autonomic regulation

Although the orexigenic effect of these peptides is less impressive than those of NPY [65] they may play a physiologically relevant role as modulators of the effects of other neuropeptides and there exist convincing anatomic and pharmacologic evidences for such interactions. Both ORX- and melanin concentrating hormone (MCH)-producing neurons in the LHA receive apparent innervation from NPY cells originating in the arcuate nucleus (ARC), suggesting to some [4] that ORX and/or MCH might mediate

Dorsal vagal complex

The data outlined above showing clear pressor effects of i.c.v. ORX [53], [72] are suggestive of the involvement of important cardiovascular centres as sites of action through which centrally administered peptide elicits such actions. The demonstration of ORX receptors and immunoreactivity in the dorsal vagal complex clearly identifies this critical autonomic nucleus as a likely locus for such ORX actions. We have undertaken microinjection studies in anaesthetized rats and have observed large,

Paraventricular nucleus

There clearly are effects of orexins in the neuroendocrine hypothalamus, where both receptor subtypes are localized [51], [77]. Indeed we have observed a dose-related stimulation of ACTH release in conscious, freely moving rats following injection of ORX-A into the lateral cerebral ventricle [69] suggesting an action of ORX-A via the OX2R receptors present in parvocellular PVN [51], which we would thus speculate to be localized on CRH neurons, a suggestion supported by the distribution of ORX

Pituitary

In addition to innervation of neuroendocrine centers of the hypothalamus such as the arcuate and paraventricular nuclei, ORX-positive fibers have been identified in both the internal and external layers of the median eminence [12]. This, plus the presence of the OX1R and OX2R receptors in anterior lobe [12], suggests a direct neuroendocrine action of the peptides in the gland in addition to possible neuromodulatory actions in hypothalamus [79]. We have conducted extensive studies in primary

Search for physiological relevance

Are the pharmacologic effects of ORX on neuroendocrine function described above physiologically relevant? Chemelli and colleagues [9] developed an ORX knockout mouse that displayed a behavioral phenotype quite similar to, but not exactly the same as, the canine and human narcolepsy models [49], [59]. These mice were, however, otherwise normal and their metabolic state similar to wild-type controls. Importantly, these mice were fertile, and thus the effects of the peptide on gonadotropin

Conclusions and perspectives

A developing literature indicates the potential for ORX producing neurons to be important contributors to the hypothalamic control of anterior pituitary function and the integrated control of autonomic function. It is now imperative that more be learned about the neural systems that control the activity of ORX producing cells in the diencehphalon, the “wiring diagram” that these neurons project into, and the significance of those synaptic contacts. Transgenic models of ORX overexpression would

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