Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

• Main Authors: Yingfeng Deng (Author), Zhao V. Wang (Author), Ruth Gordillo (Author), Yi Zhu (Author), Aktar Ali (Author), Chen Zhang (Author), Xiaoding Wang (Author), Mengle Shao (Author), Zhuzhen Zhang (Author), Puneeth Iyengar (Author), Rana K. Gupta (Author), Jay D. Horton (Author), Joseph A. Hill (Author), Philipp E. Scherer (Author)
• Format: Book
• Published: Elsevier, 2018-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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

Item Description

2212-8778
10.1016/j.molmet.2018.02.013