Transcriptional determinants of lipid mobilization in human adipocytes

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]