A link between adipogenesis and innate immunity: RNase-L promotes 3T3-L1 adipogenesis by destabilizing Pref-1 mRNA.
Ribonuclease L (RNase-L) is an endoribonuclease well known for its roles in innate immunity. Recently it has been shown to regulate several cellular functions by modulating the levels of specific mRNAs. In this study, we investigated whether RNase-L may regulate adipocyte functions. We showed that knockdown of RNase-L reduced 3T3-L1 adipocyte differentiation and lipid accumulation. After mRNA profiling, we found that upregulation of Pref-1 mRNA, an inhibitory regulator of adipogenesis, could explain the reduced adipocyte differentiation with RNase-L downregulation. The signaling molecules downstream to Pref-1, including focal adhesion kinase, extracellular signal-regulated kinases and SRY-box 9, were activated by RNase-L suppression. The presence of Pref-1 mRNA was detected in the mRNP complexes precipitated by anti-RNase-L antibody. Moreover, the Pref-1 mRNA decay rate was raised by elevated RNase-L ribonuclease activity. Finally, in stable cell clones with RNase-L silencing, suppression of Pref-1 mRNA by specific siRNA partially recovered the adipocyte differentiation phenotype. Consistent with our findings, meta-analysis of 45 public array datasets from seven independent studies showed a significant negative relationship between RNase-L and Pref-1 mRNA levels in mouse adipose tissues. Higher RNase-L and lower Pref-1 mRNAs were found in the adipose tissues of high-fat diet mice compared to those of ND mice. In line with this, our animal data also showed that the adipose tissues of obese rats contained higher RNase-L and lower Pref-1 expression in comparison to that of lean rats. This study demonstrated that Pref-1 mRNA is a novel substrate of RNase-L. RNase-L is involved in adipocyte differentiation through destabilizing Pref-1 mRNA, thus offering a new link among RNA metabolism, innate immunity and adipogenesis in obesity progression.
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yi-Ting
YT
Wang
Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Program in Metabolic Biology, Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
Hou-Hsien
HH
Chiang
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ying-Shing
YS
Huang
Department of Life Science, National Taiwan University, Taipei, Taiwan.
Chia-Lang
0000-0002-7447-8045
CL
Hsu
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.|Center for Obesity, Lifestyle and Metabolic Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Po-Jen
PJ
Yang
Department of Life Science, National Taiwan University, Taipei, Taiwan.
Hsueh-Fen
HF
Juan
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Center for Obesity, Lifestyle and Metabolic Surgery, National Taiwan University Hospital, Taipei, Taiwan.|Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Medical Genomics & Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wei-Shiung
WS
Yang
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000235:genetics / Q000276:immunology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics; D059305:Diet, High-Fat; D015536:Down-Regulation / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D007113:Immunity, Innate / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008954:Models, Biological; D009765:Obesity / Q000235:genetics; D011485:Protein Binding; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012261:Ribonucleoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease