@article{edea8e6889904c48aabb01cbe26ceda7,
title = "Adipocyte Xbp1s overexpression drives uridine production and reduces obesity",
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",
author = "Yingfeng Deng and Zhao Wang and Ruth Gordillo and Yi Zhu and Aktar Ali and Chen Zhang and Xiaoding Wang and Mengle Shao and Zhuzhen Zhang and Puneeth Iyengar and Gupta, {Rana K} and Horton, {Jay D} and Hill, {Joseph A} and Scherer, {Philipp E}",
note = "Funding Information: We thank Wei Tan (Division of Cardiology, UT Southwestern Medical Center) for excellent technical assistance. We thank Q. Liang and J. Brabander for the synthesis of PALA (Department of Biochemistry and Simmons Comprehensive Cancer Center, UT Southwestern Medical Center). This work was supported in part by a postdoctoral fellowship from the American Diabetes Association ( 7-08-MN-53 ) (to YD), a Scientist Development Grant from the American Heart Association ( 14SDG18440002 ) (to ZVW), NIH grants R01-DK55758 and R01-DK099110 and P01-AG051459 (PES), and P01-DK088761 (PES, JKE, JDH). PES was also supported by an unrestricted grant from the Novo Nordisk Research Foundation . JAH was supported by grants from the National Institutes of Health ( HL-120732, HL-128215, HL-126012 ), the American Heart Association ( 14SFRN20510023; 14SFRN20670003 ), the Fondation Leducq ( 11CVD04 ), and the Cancer Prevention and Research Institute of Texas ( RP110486P3 ). Funding Information: We thank Wei Tan (Division of Cardiology, UT Southwestern Medical Center) for excellent technical assistance. We thank Q. Liang and J. Brabander for the synthesis of PALA (Department of Biochemistry and Simmons Comprehensive Cancer Center, UT Southwestern Medical Center). This work was supported in part by a postdoctoral fellowship from the American Diabetes Association (7-08-MN-53) (to YD), a Scientist Development Grant from the American Heart Association (14SDG18440002) (to ZVW), NIH grants R01-DK55758 and R01-DK099110 and P01-AG051459 (PES), and P01-DK088761 (PES, JKE, JDH). PES was also supported by an unrestricted grant from the Novo Nordisk Research Foundation. JAH was supported by grants from the National Institutes of Health (HL-120732, HL-128215, HL-126012), the American Heart Association (14SFRN20510023; 14SFRN20670003), the Fondation Leducq (11CVD04), and the Cancer Prevention and Research Institute of Texas (RP110486P3). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = may,
doi = "10.1016/j.molmet.2018.02.013",
language = "English (US)",
volume = "11",
pages = "1--17",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
}