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Transcriptional determinants of lipid mobilization in human adipocytes [Microarray]

ABSTRACT: Defects in white adipose tissue lipolysis drive multiple aspects of cardiometabolic disease but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as: i) transcription factors, ii) histone variant chaperones, and iii) mRNA processing proteins. Based on its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on ZNF189, which encodes the Zinc Finger Protein 189. Using mass-spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of Phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2 and overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization. We performed Clariom S microarray on human adipocytes to identify genes regulated by ZNF189 depletion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247813 | GEO | 2023/11/24

REPOSITORIES: GEO

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Transcriptional determinants of lipid mobilization in human adipocytes

Project description:Defects in white adipose tissue lipolysis drive multiple aspects of cardiometabolic disease but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as: i) transcription factors, ii) histone variant chaperones, and iii) mRNA processing proteins. Based on its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on ZNF189, which encodes the Zinc Finger Protein 189. Using mass-spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of Phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2 and overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization. [Manuscript Abstract]

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Project description:Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional co-factor transducin beta-like-related (TBLR) 1 blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and when placed on a high fat diet show aggravated adiposity, glucose intolerance and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFA). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes may thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders. We used microarrays to identify global gene expression in 3T3-L1 adipocytes lacking TBLR1 and compared gene expression to control shRNA treated cells in both basal and isoproterenol stimulated states. We analyzed 12 RNA samples extracted from 3T3-L1 adipocytes that were treated with either control or TBLR1 specific shRNAs and with or without 10 ÂµM isoproterenol for 3 hrs. Three replicates of each condition.

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