Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

Yingfeng Deng; Zhao V. 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

Molecular Metabolism (May 2018)

Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

Yingfeng Deng,
Zhao V. 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

Affiliations

Yingfeng Deng: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Zhao V. Wang: Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Ruth Gordillo: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Yi Zhu: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Aktar Ali: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Chen Zhang: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Xiaoding Wang: 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
Mengle Shao: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Zhuzhen Zhang: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Puneeth Iyengar: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Rana K. Gupta: Touchstone Diabetes Center, Department of Internal Medicines, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Jay D. Horton: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
Joseph A. Hill: 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
Philipp E. Scherer: 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; Corresponding author. Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Fax: +214 648 8720.

Journal volume & issue: Vol. 11
pp. 1 – 17

Abstract

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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: Obesity, Xbp1, ER stress, UPR, Pyrimidine, Uridine, CAD

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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