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Expression of Orexin-A and Functional Orexin Type 2 Receptors in the Human Adult Adrenals: Implications for Adrenal Function and Energy Homeostasis

Sir Quinton Hazel Molecular Medicine Research Center, Department of Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL

Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, Department of Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL. E-mail: hrandeva{at}bio.warwick.ac.uk

Abstract

The hypothalamic peptides, orexin-A and orexin-B, have been implicated in the regulation of feeding behavior. In starved rats catabolic activity quickly predominates, reinforced by elevated corticosterone, independent of ACTH, implicating adrenal activity as a metabolic regulator. In view of these findings, we investigated whether orexin and orexin receptors are present in human adult adrenals and might therefore be implicated in hormonal regulation and energy homeostasis outside the central nervous system. RT-PCR, fluorescent in situ hybridization, immunoblotting, and immunostaining analysis confirmed the expression of the orexin type 2 receptor, but not of orexin type 1 receptor, in the adrenal cortex. Immunoblotting analysis also detected the presence of the prepro-orexin and its cleaved product orexin-A. Treatment of adult adrenal membranes with orexin-A increased the labeling of G_s, G_q, and, to a lesser degree, G_i, but not G_o. Stimulation with orexin-A induced cAMP and IP3 production in a dose-dependent manner. The data presented here provide conclusive evidence for the presence of orexin-A and orexin type 2 receptors in human adult adrenal glands. At the moment the functional relevance of this is uncertain. However, it is known that both orexin-A and orexin-B can induce corticosterone production in dispersed rat adrenocortical cells. Our data provide further evidence for a functional link between orexogenic signals and adrenal function. The concept that the peptide acting via these receptors in the adult adrenal is responsible for steroidogenesis and energy balance is attractive.

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