White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment

Molecular Metabolism

卷:44

Silje Bøen Torsetnes¹  Ole Nørregaard Jensen¹  Simone Sidoli²  Patricia Stephanie S. Petersen³  Morten Lundh³  Marie Sophie Isidor³  Galal Nazih Chehabi³  Marina Agueda-Oyarzabal³  Romain Barrès³  Atefeh Rabiee³  Zachary Gerhart-Hines³  Brice Emanuelli³  Erin Louise Brown³  Ali Altıntaş³  Marco Tozzi³  Kaja Plucińska³ 

[1] Department of Biochemistry and Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark;

[2] Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, Denmark;

[3] Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;

关键词: Brite/beige adipose tissue;    Adipocyte;    Browning;    Temporal proteomic;    YBX1;    Transcriptional regulation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: Increasing adaptive thermogenesis by stimulating browning in white adipose tissue is a promising method of improving metabolic health. However, the molecular mechanisms underlying this transition remain elusive. Our study examined the molecular determinants driving the differentiation of precursor cells into thermogenic adipocytes. Methods: In this study, we conducted temporal high-resolution proteomic analysis of subcutaneous white adipose tissue (scWAT) after cold exposure in mice. This was followed by loss- and gain-of-function experiments using siRNA-mediated knockdown and CRISPRa-mediated induction of gene expression, respectively, to evaluate the function of the transcriptional regulator Y box-binding protein 1 (YBX1) during adipogenesis of brown pre-adipocytes and mesenchymal stem cells. Transcriptomic analysis of mesenchymal stem cells following induction of endogenous Ybx1 expression was conducted to elucidate transcriptomic events controlled by YBX1 during adipogenesis. Results: Our proteomics analysis uncovered 509 proteins differentially regulated by cold in a time-dependent manner. Overall, 44 transcriptional regulators were acutely upregulated following cold exposure, among which included the cold-shock domain containing protein YBX1, peaking after 24 h. Cold-induced upregulation of YBX1 also occurred in brown adipose tissue, but not in visceral white adipose tissue, suggesting a role of YBX1 in thermogenesis. This role was confirmed by Ybx1 knockdown in brown and brite preadipocytes, which significantly impaired their thermogenic potential. Conversely, inducing Ybx1 expression in mesenchymal stem cells during adipogenesis promoted browning concurrent with an increased expression of thermogenic markers and enhanced mitochondrial respiration. At a molecular level, our transcriptomic analysis showed that YBX1 regulates a subset of genes, including the histone H3K9 demethylase Jmjd1c, to promote thermogenic adipocyte differentiation. Conclusion: Our study mapped the dynamic proteomic changes of murine scWAT during browning and identified YBX1 as a novel factor coordinating the genomic mechanisms by which preadipocytes commit to brite/beige lineage.

【 授权许可】

Unknown