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

Adipocyte Xbp1s overexpression drives uridine production and reduces obesity.

Author information

1
Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
2
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
3
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
4
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
5
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
6
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
7
Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: Philipp.Scherer@utsouthwestern.edu.

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

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