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ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE175655 | GEO | 2022/05/01

REPOSITORIES: GEO

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ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes.

Project description:Energy-storing white adipocytes maintain their identity by suppressing the energy-burning thermogenic gene program of brown and beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional coregulator ZFP423 and brown fat determination factor EBF2 is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread "browning" of WAT in adult mice. Mechanistically, ZFP423 recruits the NuRD corepressor complex to EBF2-bound thermogenic gene enhancers. Loss of adipocyte Zfp423 induces an EBF2 NuRD-to-BAF coregulator switch and a shift in PPARγ occupancy to thermogenic genes. This shift in PPARγ occupancy increases the antidiabetic efficacy of the PPARγ agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes and highlight the potential of therapeutically targeting transcriptional brakes to induce beige adipocyte biogenesis in obesity.

| S-EPMC8559675 | biostudies-literature

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChIP-seq

Project description:Energy-storing white adipocytes maintain their identity by suppressing the gene program defining energy-burning thermogenic brown/beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional co-regulator ZFP423 and brown/beige cell determination factor, EBF2, is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread “browning” of WAT in adult mice. Mechanistically, adipocyte Zfp423 deficiency induces an EBF2 NuRD-to-BAF co-regulator switch and a shift in PPARgamma occupancy to thermogenic genes. This shift in PPARgamma occupancy increases the anti-diabetic efficacy of the PPARgamma agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 co-activator recruitment and PPARgamma occupancy to determine the thermogenic plasticity of adipocytes and raise the concept of targeting transcriptional brakes in adipocyte gene expression as a therapeutic strategy to induce thermogenic adipocyte biogenesis in obesity.

2022-05-01 | GSE175654 | GEO

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChAP-seq

2022-05-01 | GSE175653 | GEO

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes

Project description:ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes

| PRJNA733147 | ENA

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChAP-seq

Project description:ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChAP-seq

| PRJNA733155 | ENA

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChIP-seq

Project description:ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChIP-seq

| PRJNA733156 | ENA

EBF2 promotes the recruitment of beige adipocytes in white adipose tissue.

Project description:OBJECTIVE:The induction of beige/brite adipose cells in white adipose tissue (WAT) is associated with protection against high fat diet-induced obesity and insulin resistance in animals. The helix-loop-helix transcription factor Early B-Cell Factor-2 (EBF2) regulates brown adipose tissue development. Here, we asked if EBF2 regulates beige fat cell biogenesis and protects animals against obesity. METHODS:In addition to primary cell culture studies, we used ?Ebf2 knockout mice and mice overexpressing EBF2 in the adipose tissue to study the necessity and sufficiency of EBF2 to induce beiging in vivo. RESULTS:We found that EBF2 is required for beige adipocyte development in mice. Subcutaneous WAT or primary adipose cell cultures from Ebf2 knockout mice did not induce Uncoupling Protein 1 (UCP1) or a thermogenic program following adrenergic stimulation. Conversely, over-expression of EBF2 in adipocyte cultures induced UCP1 expression and a brown-like/beige fat-selective differentiation program. Transgenic expression of Ebf2 in adipose tissues robustly stimulated beige adipocyte development in the WAT of mice, even while housed at thermoneutrality. EBF2 overexpression was sufficient to increase mitochondrial function in WAT and protect animals against high fat diet-induced weight gain. CONCLUSIONS:Taken together, our results demonstrate that EBF2 controls the beiging process and suggest that activation of EBF2 in WAT could be used to reduce obesity.

| S-EPMC4703852 | biostudies-literature

EBF2 promotes the recruitment of beige adipocytes in white adipose tissue

Project description:The induction of beige/brite adipose cells in white adipose tissue (WAT) is associated with protection against high fat diet-induced obesity and insulin resistance in animals. The helix-loop-helix transcription factor Early B-Cell Factor-2 (EBF2) regulates brown adipose tissue development. We examined the role of EBF2 in beige fat cell biogenesis by comparing transcriptome in wildtype and EBF2-overexpressing mice in the adipose tissue. Four control replicates (wildtype) and four experimental replicates (Fabp4-Ebf2) mice were analyzed

2015-12-31 | E-GEOD-74366 | biostudies-arrayexpress

EBF2 promotes the recruitment of beige adipocytes in white adipose tissue

2015-12-31 | GSE74366 | GEO

Transferrin Receptor Functionally Marks Thermogenic Adipocytes.

Project description:BackgroundThermogenic adipocytes, including beige and brown adipocytes, are critical for thermogenesis and energy homeostasis. Identification of functional cell surface markers of thermogenic adipocytes is of significance for potential application in biological and clinical practices.MethodsWith a combination of RNA-sequencing of in vivo and in vitro models, we identified transferrin receptor (Tfr1), a receptor specialized for cellular iron uptake, as a previously unappreciated cell surface molecule for thermogenic adipocytes compared to white adipocytes. The alternation of Tfr1 levels under physiological and pathological stimuli was assessed, and the mitochondria functionality, browning capacity, and iron metabolism of mature adipocytes were examined with Tfr1 knockdown.ResultsTfr1 was expressed predominantly in thermogenic adipocytes versus white adipocyte, and its expression levels were tightly correlated with the activation or inhibition status of thermogenic adipocytes under external stimuli. Besides, Tfr1 gene deficiency in thermogenic adipocytes led to reduced thermogenic gene programs and mitochondrial integrity.ConclusionTfr1 functionally marks thermogenic adipocytes and could serve as a potential thermogenic adipocyte surface marker.

| S-EPMC7676909 | biostudies-literature

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