Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

Yingfeng Deng, Zhao Wang, Ruth Gordillo, Yi Zhu, Aktar Ali, Chen Zhang, Xiaoding Wang, Mengle Shao, Zhuzhen Zhang, Puneeth Iyengar, Rana K Gupta, Jay D Horton, Joseph A Hill, Philipp E Scherer

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Objective: The spliced transcription factor Xbp1 (Xbp1s), a transducer of the unfolded protein response (UPR), regulates lipolysis. Lipolysis is stimulated by fasting when uridine synthesis is also activated in adipocytes. Methods: Here we have examined the regulatory role Xbp1s in stimulation of uridine biosynthesis in adipocytes and triglyceride mobilization using inducible mouse models. Results: Xbp1s is a key molecule involved in adipocyte uridine biosynthesis and release by activation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD), the rate-limiting enzyme for UMP biosynthesis. Adipocyte Xbp1s overexpression drives energy mobilization and protects mice from obesity through activation of the pyrimidine biosynthesis pathway. Conclusion: These observations reveal that Xbp1s is a potent stimulator of uridine production in adipocytes, enhancing lipolysis and invoking a potential anti-obesity strategy through the induction of a futile biosynthetic cycle.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalMolecular Metabolism
Volume11
DOIs
StatePublished - May 2018

Keywords

  • CAD
  • ER stress
  • Obesity
  • Pyrimidine
  • UPR
  • Uridine
  • Xbp1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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