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 8

NR4A1 regulates AP function and systemic glucose homeostasis in obesity.

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NR4A1 regulates AP function and systemic glucose homeostasis in obesity....
(A) Protocol of AP transplantation and high-fat feeding for adult (10 weeks old) C57BL/6 mice. (B) Weight gain expressed as percentage of initial body weight of the mice after Nr4a1+/+ or Nr4a1–/– AP transplantation and 10 weeks of HFF. (C) Evolution of the AUC of glucose tolerance test (GTT) during HFF and after AP transplantation. (D) Evolution of the AUC of insulin tolerance test (ITT) during HFF and after AP transplantation. (E) i.p. (1.5 g/kg) GTT from the 10-week time point shown in C. (F) i.p. (0.5 U/kg) ITT from the 10-week time point shown in D. (G) Glucose measured after 4-hour fast. (H) Serum insulin levels after 4-hour fast. (I) HOMA-IR derived from glucose/insulin as shown in H and I. (J) Serum NEFA. (K) Liver TG content. (L) Inguinal (SAT) and perigonadal (VAT) depot weights. (M) Adipocyte mean cross-sectional areas (CSA) for SAT (left) and VAT (right). (B–M) n = 5, data expressed as mean ± SEM. Significance was assessed by 2-tailed, unpaired t test. *P < 0.05; **P < 0.01; ***P < 0.001.