Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells.

Naoko Tsukamoto-Yamauchi,Motoshi Komatsubara,Nahoko Iwata,Fumio Otsuka,Takahiro Nada,Satoshi Fujisawa,Jun Wada

doi:10.3390/ijms22094553

Naoko Tsukamoto-Yamauchi, Motoshi Komatsubara + Show 5 more

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https://doi.org/10.3390/ijms22094553

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Abstract

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic–pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

Highlights

We previously reported that bone morphogenetic protein (BMP)-4 was involved in the suppression of ACTH secretion by somatostatin receptor stimulation and suppressed GHRP-2-induced ACTH secretion in AtT20 cells [20,21]
We investigated the role of orexin in endocrine regulation in the pituitary gland, focusing on the relationship of orexin with BMP signaling by using the mouse pituitary corticotrope tumor cell line AtT20
AtT20 cells express CRH receptor type-1 (CRHR1) as a receptor for corticotropin-releasing hormone (CRH), and orexin A (100 nM) treatment enhanced the mRNA expression of CRHR1

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Orexins are neuropeptides that are expressed primarily in the hypothalamus and are produced in two isoforms, orexin A (ORX) and orexin B, from a common precursor protein, prepro-orexin [1]. There are two types of G protein-coupled receptors, named orexin type 1 (OX1R) and type 2 (OX2R) receptors. Since its discovery in 1998, orexin has been reported to have various effects on sleep–wake regulation, feeding behavior, emotions, and the autonomic nervous system involved in stress control [1,3,4]. Orexin is known to have physiological effects in peripheral tissues, including the endocrine system [5]

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