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Thrap3 docks on phosphoserine 273 of PPARγ and controls diabetic gene programming.

Abstract
Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARγ when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARγ. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARγ in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.
AuthorsJang Hyun Choi, Sun-Sil Choi, Eun Sun Kim, Mark P Jedrychowski, Yong Ryoul Yang, Hyun-Jun Jang, Pann-Ghill Suh, Alexander S Banks, Steven P Gygi, Bruce M Spiegelman
JournalGenes & development (Genes Dev) Vol. 28 Issue 21 Pg. 2361-9 (Nov 01 2014) ISSN: 1549-5477 [Electronic] United States
PMID25316675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2014 Choi et al.; Published by Cold Spring Harbor Laboratory Press.
Chemical References
  • Adipokines
  • DNA-Binding Proteins
  • PPAR gamma
  • THRAP3 protein, human
  • Transcription Factors
  • Phosphoserine
  • Cyclin-Dependent Kinase 5
Topics
  • 3T3 Cells
  • Adipokines (genetics)
  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase 5 (genetics, metabolism)
  • DNA-Binding Proteins (genetics)
  • Diabetes Mellitus, Type 2 (genetics)
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR gamma (metabolism)
  • Phosphorylation
  • Phosphoserine (metabolism)
  • Protein Binding
  • Transcription Factors (genetics)

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