White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment
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- White adipose remodeling during browning in mice involves YBX1 to drive thermogenic commitment
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OBJECTIVE: Increasing adaptive thermogenesis by stimulating browning in white adipose tissue is a promising way to improve metabolic health. However, the molecular mechanisms underlying this transition remain elusive. The aim of our study was to examine the molecular determinants driving the differentiation of precursor cells into thermogenic adipocytes.
METHODS: Here, we performed 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 in mesenchymal stem cells following induction of endogenous Ybx1 expression was performed to uncover the transcriptomic events controlled by YBX1 during adipogenesis.
RESULTS: Our proteomics analysis uncovered 509 proteins differentially regulated by cold in a time dependent manner. 44 transcriptional regulators were acutely upregulated following cold exposure, among which, included the cold-shock domain containing protein YBX1, peaking after 24 hours. Cold-induced upregulation of YBX1 also occurred in brown adipose tissue, but not in visceral white adipose tissue, suggesting a role for YBX1 in thermogenesis. Such a role was confirmed by Ybx1 knockdown in brown and brite preadipocytes, which greatly impaired their thermogenic potential. Conversely, inducing Ybx1 expression in mesenchymal stem cells during adipogenesis promoted browning, concurrent with 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.
|Number of pages||17|
|Publication status||Published - 2021|
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