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 5

NR4A1 regulation of adipogenesis is dependent on an intact DBD.

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NR4A1 regulation of adipogenesis is dependent on an intact DBD. ORO stai...
ORO staining after retroviral overexpression of WT Nr4a1 or DBD mutants (shown in schematic, bottom left) during expansion and differentiation of AP from Nr4a1–/– mice. Data collected after 8 days of adipogenic differentiation. Scale bar: 1 mm. Bottom right shows relative quantification at 520 nm absorbance after ORO extraction was normalized to MSCV-vector control and expressed as mean of technical replicates. Three independent experiments are shown as box (with mean line) and whiskers (minimum to maximum). Significance was assessed by 1-way ANOVA with Tukey’s adjustment for multiple comparisons. ***P < 0.001.