RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs
Jiexin Wang ... Douglas L. Black, Peter Tontonoz
Jiexin Wang ... Douglas L. Black, Peter Tontonoz
Published March 1, 2017
Citation Information: J Clin Invest. 2017;127(3):987-1004. doi:10.1172/JCI89484.
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Categories: Research Article Metabolism

RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs

Abstract

A highly orchestrated gene expression program establishes the properties that define mature adipocytes, but the contribution of posttranscriptional factors to the adipocyte phenotype is poorly understood. Here we have shown that the RNA-binding protein PSPC1, a component of the paraspeckle complex, promotes adipogenesis in vitro and is important for mature adipocyte function in vivo. Cross-linking and immunoprecipitation followed by RNA sequencing revealed that PSPC1 binds to intronic and 3′-untranslated regions of a number of adipocyte RNAs, including the RNA encoding the transcriptional regulator EBF1. Purification of the paraspeckle complex from adipocytes further showed that PSPC1 associates with the RNA export factor DDX3X in a differentiation-dependent manner. Remarkably, PSPC1 relocates from the nucleus to the cytoplasm during differentiation, coinciding with enhanced export of adipogenic RNAs. Mice lacking PSPC1 in fat displayed reduced lipid storage and adipose tissue mass and were resistant to diet-induced obesity and insulin resistance due to a compensatory increase in energy expenditure. These findings highlight a role for PSPC1-dependent RNA maturation in the posttranscriptional control of adipose development and function.

Authors

Jiexin Wang, Prashant Rajbhandari, Andrey Damianov, Areum Han, Tamer Sallam, Hironori Waki, Claudio J. Villanueva, Stephen D. Lee, Ronni Nielsen, Susanne Mandrup, Karen Reue, Stephen G. Young, Julian Whitelegge, Enrique Saez, Douglas L. Black, Peter Tontonoz

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Adipose-specific PSPC1-deficient mice are resistant to diet-induced obes...

Figure 8

Adipose-specific PSPC1-deficient mice are resistant to diet-induced obesity.

(A) Body weight of Pspc1fl/fl (F/F) and Pspc1fl/fl Cre+ (KO) mice fed chow diet for 10 weeks and then switched to 60% HFD. n = 8 per group, female mice. Statistical analysis was performed using Student’s t test. (B) External appearance of representative F/F and KO mice shown in A at 20 weeks of age after 10 weeks on HFD. (C) Body fat and lean mass in F/F and KO mice at 8 weeks old on chow diet and at 20 weeks old after 10 weeks on HFD determined by EchoMRI. n = 8 per group, female mice. Comparison was made against F/F control mice by Student’s t test. (D) Average weight of individual white and brown adipose fat pads from F/F and KO mice after 10 weeks on HFD. n = 8 per group, 20-week-old female mice. Comparison was made against F/F control mice by Student’s t test. (E) Representative F/F and KO mice after 10 weeks on HFD showing grossly reduced adipose tissue content in the absence of PSPC1. (F) Gross appearance of tissues from F/F and KO mice after 10 weeks on HFD. (G) Histology of tissues from F/F and KO mice after 10 weeks on HFD. Results are representative of 2 independent cohorts of mice. Scale bars: iWAT and epididymal white adipose tissue (eWAT), 100 μm; BAT and liver, 50 μm. Error bars represent mean + SEM. *P < 0.05, **P < 0.01.