@article{c121ed44509d4105b6725304e3b10245,
title = "ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes",
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.",
keywords = "Beige adipocytes, EBF2, PPARγ, Rosiglitazone, White adipocytes], ZFP423",
author = "Mengle Shao and Qianbin Zhang and Ashley Truong and Bo Shan and Lavanya Vishvanath and Lin Li and Patrick Seale and Gupta, {Rana K.}",
note = "Funding Information: We are grateful to members of the University of Texas Southwestern Touchstone Diabetes Center for useful discussions. We thank Charlotte Lee, the University of Texas Southwestern Animal Resource Center, Metabolic Phenotyping Core, Pathology Core, Live-Cell Imaging Core, Flow Cytometry Core, and McDermott Sequencing Center for excellent guidance and assistance with experiments performed here. We thank the University of Texas Southwestern Children's Research Institute Mouse Genome Engineering Core for generating the Zfp423WT-Avi and Zfp423H1285-Avi genetic strains. This study and/or personnel were supported in part by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK104789, R01 DK119163, and RC2 DK118620 to R.K.G.; American Heart Association postdoctoral fellowship 16POST26420136 and Career Development Award 19CDA34670007 from the American Heart Association and the Harry S. Moss Heart Trust to M.S.; and NIDDK R01 DK121801 and DK123356 to P.S. Funding Information: We are grateful to members of the University of Texas Southwestern Touchstone Diabetes Center for useful discussions. We thank Charlotte Lee, the University of Texas Southwestern Animal Resource Center, Metabolic Phenotyping Core, Pathology Core, Live-Cell Imaging Core, Flow Cytometry Core, and McDermott Sequencing Center for excellent guidance and assistance with experiments performed here. We thank the University of Texas Southwestern Children{\textquoteright}s Research Institute Mouse Genome Engineering Core for generating the Zfp423WT-Avi and Zfp423H1285-Avi genetic strains. This study and/or personnel were supported in part by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK104789, R01 DK119163, and RC2 DK118620 to R.K.G.; American Heart Association postdoctoral fellowship 16POST26420136 and Career Development Award 19CDA34670007 from the American Heart Association and the Harry S. Moss Heart Trust to M.S.; and NIDDK R01 DK121801 and DK123356 to P.S. Publisher Copyright: {\textcopyright} 2021 Shao et al.",
year = "2021",
month = nov,
day = "1",
doi = "10.1101/GAD.348780.121",
language = "English (US)",
volume = "35",
pages = "1461--1474",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "21-22",
}