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

Jang 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

doi:10.1101/gad.249367.114

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

¹Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea;
²Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
³Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
⁴Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

Corresponding authors: bruce_spiegelman{at}dfci.harvard.edu, janghchoi{at}unist.ac.kr

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.

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Footnotes

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.249367.114.

Received July 21, 2014.
Accepted September 26, 2014.

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