Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

Yingfeng Deng, Zhao 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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Uridine
Adipocytes
Obesity
Lipolysis
Dihydroorotase
Aspartate Carbamoyltransferase
Substrate Cycling
Carbamyl Phosphate
Uridine Monophosphate
Unfolded Protein Response
Ligases
Transducers
Fasting
Triglycerides
Transcription Factors
Drive
Enzymes

Keywords

  • CAD
  • ER stress
  • Obesity
  • Pyrimidine
  • UPR
  • Uridine
  • Xbp1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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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}",
year = "2018",
month = "1",
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doi = "10.1016/j.molmet.2018.02.013",
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TY - JOUR

T1 - Adipocyte Xbp1s overexpression drives uridine production and reduces obesity

AU - Deng, Yingfeng

AU - Wang, Zhao

AU - Gordillo, Ruth

AU - Zhu, Yi

AU - Ali, Aktar

AU - Zhang, Chen

AU - Wang, Xiaoding

AU - Shao, Mengle

AU - Zhang, Zhuzhen

AU - Iyengar, Puneeth

AU - Gupta, Rana K

AU - Horton, Jay D

AU - Hill, Joseph A

AU - Scherer, Philipp E

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - CAD

KW - ER stress

KW - Obesity

KW - Pyrimidine

KW - UPR

KW - Uridine

KW - Xbp1

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