Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity
Yang Zhang, Alexander J. Federation, Soomin Kim, John P. O’Keefe, Mingyue Lun, Dongxi Xiang, Jonathan D. Brown, Matthew L. Steinhauser
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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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 7

Nr4a1 regulates adipogenesis in vivo.

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Nr4a1 regulates adipogenesis in vivo. (A) Two cohorts of juvenile (4 wee...
(A) Two cohorts of juvenile (4 weeks old) Nr4a1+/+ and Nr4a1–/– male mice labeled for 2 weeks with 15N-thymidine. Relative labeling in stromal vascular cells from SAT and VAT (line indicates mean). Significance was assessed by 2-tailed, unpaired t test. (B) Three cohorts of juvenile (4 weeks old) Nr4a1+/+ and Nr4a1–/– male mice labeled for 2 weeks with15N-thymidine. Relative labeling in adipocyte fractions isolated from SAT and VAT (line indicates mean). Significance was assessed by 2-tailed, unpaired t test. (C) Adult (10 weeks old) Nr4a1+/+ and Nr4a1–/– mice receiving normal chow or high-fat feeding (HFF) were labeled for 8 weeks with15N-thymidine. Relative labeling in the adipocyte fractions isolated from SAT and VAT (line indicates mean). Two-way ANOVA, Šidák’s multiple comparisons adjustment. *P < 0.05; **P < 0.01; ***P < 0.001.