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Pharmacological and genetic modulation of REV-ERB activity and expression affects orexigenic gene expression

Academic Article
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Overview

related to degree

  • Amador, Ariadna, Ph.D. in Molecular Therapeutics, Scripps Research 2010 - 2016

authors

  • Amador, Ariadna
  • Wang, Y.
  • Banerjee, S.
  • Kamenecka, Theodore
  • Solt, Laura A.
  • Burris, Thomas

publication date

  • 2016

journal

  • PLoS One  Journal

abstract

  • The nuclear receptors REV-ERB? and REV-ERB? are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERB?-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.
  • The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.

subject areas

  • Animals
  • Brain
  • Gene Deletion
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Orexins
  • Pyrrolidines
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Thiophenes
  • Transcriptional Activation
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Identity

PubMed Central ID

  • PMC4786293

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0151014

PubMed ID

  • 26963516
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Additional Document Info

volume

  • 11

issue

  • 3

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