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

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75 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. How white adipocytes suppress their thermogenic gene program has remained unclear. Here, Shao et al. identify Zfp423 as a molecular brake on adipocyte thermogenesis through inhibition of Ebf2 activity. Inducible deletion of Zfp423 in obese mice triggers white-to-beige adipocyte reprogramming and reversal of obesity and insulin resistance.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
Publication statusAccepted/In press - Nov 9 2015

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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