Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

Mol Metab. 2018 May;11:1-17. doi: 10.1016/j.molmet.2018.02.013. Epub 2018 Mar 2.

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.

Keywords: CAD; ER stress; Obesity; Pyrimidine; UPR; Uridine; Xbp1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / metabolism*
  • Animals
  • Cells, Cultured
  • Lipolysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism*
  • Uridine / metabolism*
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism*

Substances

  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Uridine