The orphan nuclear receptor RORalpha restrains adipocyte differentiation through a reduction of C/EBPbeta activity

Nobumichi Ohoka1, Shogo Kato, Yu Takahashi

  • 1Department of Applied Biological Chemistry, The University of Tokyo, Japan.

Insights

Retinoic acid receptor-related orphan receptor alpha (RORalpha) inhibits adipocyte differentiation by blocking key transcription factors. RORalpha negatively regulates adipogenesis through dual mechanisms, impacting C/EBPbeta and PPARgamma activity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Endocrinology

Background:

  • Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a transcription factor involved in various cellular functions.
  • The precise role of RORalpha in adipocyte differentiation remains incompletely understood.

Purpose of the Study:

  • To elucidate the role and mechanism of RORalpha in regulating adipocyte differentiation.

Main Methods:

  • Investigated the interaction between RORalpha and CCAAT/enhancer-binding protein beta (C/EBPbeta).
  • Assessed the impact of RORalpha on the expression of adipogenic genes like PPARgamma and C/EBPalpha.
  • Analyzed the effect of RORalpha on perilipin gene expression and its promoter activity.
  • Examined the competitive antagonism between RORalpha and peroxisome proliferators-activated receptor gamma (PPARgamma).

Main Results:

  • RORalpha suppresses C/EBPbeta transcriptional activity, inhibiting C/EBPbeta-dependent adipogenesis.
  • RORalpha represses the association of C/EBPbeta with p300 and its recruitment to chromatin.
  • RORalpha antagonizes PPARgamma activity by binding to a suppressive ROR-responsive element in the perilipin promoter, thus inhibiting perilipin induction.
  • RORalpha acts as a negative regulator of adipocyte differentiation through these dual mechanisms.

Conclusions:

  • RORalpha is identified as a novel negative regulator of adipocyte differentiation.
  • RORalpha inhibits adipogenesis by interfering with both C/EBPbeta and PPARgamma signaling pathways.
  • These findings provide new insights into the molecular mechanisms controlling adipocyte development.

Related Concept Videos

Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...