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

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 b-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.