Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity
Yang Zhang, … , Jonathan D. Brown, Matthew L. Steinhauser
Yang Zhang, … , Jonathan D. Brown, Matthew L. Steinhauser
Published October 2, 2018
Citation Information: J Clin Invest. 2018;128(11):4898-4911. https://doi.org/10.1172/JCI98353.
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Research Article Cell biology Metabolism

Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity

Abstract

Adipocyte turnover in adulthood is low, suggesting that the cellular source of new adipocytes, the adipocyte progenitor (AP), resides in a state of relative quiescence. Yet the core transcriptional regulatory circuitry (CRC) responsible for establishing a quiescent state and the physiological significance of AP quiescence are incompletely understood. Here, we integrate transcriptomic data with maps of accessible chromatin in primary APs, implicating the orphan nuclear receptor NR4A1 in AP cell-state regulation. NR4A1 gain and loss of function in APs ex vivo decreased and enhanced adipogenesis, respectively. Adipose tissue of Nr4a1–/– mice demonstrated higher proliferative and adipogenic capacity compared with that of WT mice. Transplantation of Nr4a1–/– APs into the subcutaneous adipose tissue of WT obese recipients improved metrics of glucose homeostasis relative to administration of WT APs. Collectively, these data identify NR4A1 as a previously unrecognized constitutive regulator of AP quiescence and suggest that augmentation of adipose tissue plasticity may attenuate negative metabolic sequelae of obesity.

Authors

Yang Zhang, Alexander J. Federation, Soomin Kim, John P. O’Keefe, Mingyue Lun, Dongxi Xiang, Jonathan D. Brown, Matthew L. Steinhauser

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Figure 6

Nr4a1 regulates a cell-cycle transcriptional program.

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Nr4a1 regulates a cell-cycle transcriptional program. (A) Volcano plots ...
(A) Volcano plots of RNA-seq conducted on AP from Nr4a1+/+ (WT) and Nr4a1–/– (KO) mice (n = 4 mice). Red dots, positively regulated genes in KO group (adjusted P < 0.05); blue dots, negatively regulated genes in KO group (adjusted P < 0.05). (B) Venn diagrams show overlap of differentially expressed genes in APs from 2 adipose depots. (C) Hierarchical clustering analysis of common differentially expressed genes from the 2 adipose depots (198 genes). (D) GSEA enrichment plots for GO cell cycle (see also Supplemental Figure 4) in APs from Nr4a1-KO mice (P < 0.001) relative to WT. (E) Fold change of all genes in the TF network (Figure 1) versus all other expressed genes. TF network genes are as a group downregulated in KO group relative to all other expressed genes. **P < 0.01, Mann-Whitney U test.