CM-Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program.pdf

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