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 November 2, 2018; First published October 2, 2018
Citation Information: J Clin Invest. 2018;128(11):4898-4911. https://doi.org/10.1172/JCI98353.
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Categories: 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 1

Identification of candidate transcriptional regulators of AP function.

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Identification of candidate transcriptional regulators of AP function. (...
(A and B) Relative adipogenesis measured as a function of postnatal age. 15N-thymidine administered for 2 weeks to mice of various ages ranging from less than 24 hours old to 15 weeks old. 15N-label in the adipocyte fraction, indicative of proliferating and differentiating APs, was measured by IRMS. Relative mass provided as reference in red (see also Supplemental Figure 1, A and B). Data expressed as mean ± SEM. n = 4–11 mice per time point. (C) Microarray analyses of freshly isolated AP-rich stromal vascular fractions (see also Supplemental Figure 1C) relative to whole AT from the same mice (n = 3 mice). Heatmap representation of top 150 upregulated AP genes and 7 representative adipocyte markers in subcutaneous (S) and visceral (V) depots. (D) Left: Venn diagram of the overlap of the top 150 genes between AT depots. Right: TF fraction of the top 150 genes. (E) Top 5 GO terms for biological processes of differently expressed genes annotated by DAVID. (F) Real-time qPCR of freshly isolated APs, inclusive of the 22 TFs in C and expressed relative to unfractionated AT. (G) Relative expression of terminal adipocyte markers in APs relative to unfractionated AT. (F and G) Data displayed as bar graphs ±  SEM, with dots showing individual values; n = 4 mice. *P < 0.05, 2-tailed, unpaired t test (pass Shapiro-Wilk normality test) and Mann-Whitney U test (values are not from Gaussian distribution).