2. Academic Validation
  3. Transcriptional determinants of lipid mobilization in human adipocytes

Transcriptional determinants of lipid mobilization in human adipocytes

  • Sci Adv. 2024 Jan 5;10(1):eadi2689. doi: 10.1126/sciadv.adi2689.
Alison C Ludzki 1,  Mattias Hansen 1,  Danae Zareifi 1,  Jutta Jalkanen 1,  Zhiqiang Huang 2,  Muhmmad Omar-Hmeadi 1,  Gianluca Renzi 1,  Felix Klingelhuber 3 4,  Sebastian Boland 5,  Yohannes A Ambaw 5 6,  Na Wang 1,  Anastasios Damdimopoulos 2,  Jianping Liu 1,  Tomas Jernberg 7,  Paul Petrus 1,  Peter Arner 1,  Natalie Krahmer 3 4,  Rongrong Fan 2,  Eckardt Treuter 2,  Hui Gao 2,  Mikael Rydén 1,  Niklas Mejhert 1
Affiliations

Affiliations

  • 1 Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
  • 2 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden.
  • 3 Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany.
  • 4 Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 5 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • 6 Department of Cell Biology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
  • 7 Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, SE-182 88 Stockholm, Sweden.
PMID: 38170777 DOI: 10.1126/sciadv.adi2689
Abstract

Defects in adipocyte 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 chaperones, and (iii) mRNA processing proteins. On the basis of its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on one hit, 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 the 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.

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