title: Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program.
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.
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Mengle
authors.initials: M
authors.lastname: Shao
authors.affiliation: Institute for Diabetes, Obesity and Metabolism and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Ishibashi
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qiong A
authors.initials: QA
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Hepler
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Vishvanath
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Karen A
authors.initials: KA
authors.lastname: MacPherson
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Spurgin
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Institute for Diabetes, Obesity and Metabolism and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Seale
authors.affiliation: Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: rana.gupta@utsouthwestern.edu.
authors.forename: Rana K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D052438:Adipocytes, White / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D003080:Cold Temperature; D004268:DNA-Binding Proteins / Q000378:metabolism*; D059305:Diet, High-Fat; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D022702:Receptors, Adrenergic, beta-3; D014157:Transcription Factors; C489922:Ebf2 protein, mouse; C484557:Ebfaz protein, mouse