ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes

Mengle Shao, Qianbin Zhang, Ashley Truong, Bo Shan, Lavanya Vishvanath, Lin Li, Patrick Seale, Rana K. Gupta

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Energy-storing white adipocytes maintain their identity by suppressing the energy-burning thermogenic gene program of brown and beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional coregulator ZFP423 and brown fat determination factor EBF2 is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread “browning” of WAT in adult mice. Mechanistically, ZFP423 recruits the NuRD corepressor complex to EBF2-bound thermogenic gene enhancers. Loss of adipocyte Zfp423 induces an EBF2 NuRD-to-BAF coregulator switch and a shift in PPARγ occupancy to thermogenic genes. This shift in PPARγ occupancy increases the antidiabetic efficacy of the PPARγ agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes and highlight the potential of therapeutically targeting transcriptional brakes to induce beige adipocyte biogenesis in obesity.

Original languageEnglish (US)
Pages (from-to)1461-1474
Number of pages14
JournalGenes and Development
Volume35
Issue number21-22
DOIs
StatePublished - Nov 1 2021
Externally publishedYes

Keywords

  • Beige adipocytes
  • EBF2
  • PPARγ
  • Rosiglitazone
  • White adipocytes]
  • ZFP423

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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