Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program

Mengle Shao, Jeff Ishibashi, Christine Kusminski, Qiong A. Wang, Chelsea Hepler, Lavanya Vishvanath, Karen A. MacPherson, Stephen B. Spurgin, Kai Sun, William L Holland, Patrick Seale, Rana K Gupta

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white adipocytes to suppress the thermogenic gene program and maintain an energy-storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown adipocytes and suppressed upon cold exposure. Doxycycline-inducible inactivation of Zfp423 in mature adipocytes, combined with β-adrenergic stimulation, triggers a conversion of differentiated adiponectin-expressing inguinal and gonadal adipocytes into beige-like adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white adipocytes in obesity.

Original languageEnglish (US)
Pages (from-to)1167-1184
Number of pages18
JournalCell Metabolism
Volume23
Issue number6
DOIs
StatePublished - Jun 14 2016

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Shao, M., Ishibashi, J., Kusminski, C., Wang, Q. A., Hepler, C., Vishvanath, L., MacPherson, K. A., Spurgin, S. B., Sun, K., Holland, W. L., Seale, P., & Gupta, R. K. (2016). Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program. Cell Metabolism, 23(6), 1167-1184. https://doi.org/10.1016/j.cmet.2016.04.023