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 4

NR4A1 regulates AP differentiation in vitro.

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NR4A1 regulates AP differentiation in vitro. (A) ORO staining after indu...
(A) ORO staining after induction of adipogenesis in primary APs isolated from SAT and VAT and transduced with retroviral vectors driving overexpression of Nr4a1 (MSCV-Nr4a1) or vector control (MSCV-vector). Data collected after 8 days of adipogenic differentiation. 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. Significance was assessed by 2-tailed, paired t test. Scale bar: 1 mm. (B) qPCR analysis of relative expression of Nr4a1 and late adipogenic genes after Nr4a1 overexpression as in A. Data displayed as bar graphs ± SEM with dots showing individual values. n = 5–6 technical replicates. *P < 0.05; ***P < 0.001, 2-tailed unpaired t test. (C) ORO staining after adipogenic differentiation of APs isolated from SAT and VAT of Nr4a1+/+ and Nr4a1–/– mice. Data collected after 8 days of adipogenic differentiation. Relative quantification at 520 nm absorbance after ORO extraction was normalized to Nr4a1+/+ and expressed as mean of technical replicates. Seven independent experiments are shown. Significance was assessed by 2-tailed, paired t test. Scale bar: 1 mm. (D) qPCR analysis of late adipogenic genes in AP isolated from SAT and VAT of Nr4a1+/+ and Nr4a1–/– mice after induction of adipogenesis. Data displayed as bar graphs ± SEM with dots showing individual values. n = 3–4 technical replicates. *P < 0.05; **P < 0.01, 2-tailed unpaired t test.