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

被引：48

作者：

Choi, Jang Hyun ^{[1
]}

Choi, Sun-Sil ^{[1
]}

Kim, Eun Sun ^{[1
]}

Jedrychowski, Mark P. ^{[2
]}

Yang, Yong Ryoul ^{[1
]}

Jang, Hyun-Jun ^{[1
]}

Suh, Pann-Ghill ^{[1
]}

Banks, Alexander S. ^{[3
]}

Gygi, Steven P. ^{[2
]}

Spiegelman, Bruce M. ^{[4
]}

机构：

[1] Ulsan Natl Inst Sci & Technol, Dept Biol Sci, Ulsan 689798, South Korea

[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

来源：

GENES & DEVELOPMENT | 2014年 / 28卷 / 21期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

PPAR gamma; phosphorylation; Thrap3; interaction; gene reprogramming; energy homeostasis; THYROID-HORMONE; NUCLEAR RECEPTORS; ADIPOSE-TISSUE; INSULIN-RESISTANCE; RETINOIC ACID; OBESITY; LIGAND; COACTIVATOR; INTERACTS; ADIPSIN;

D O I：

10.1101/gad.249367.114

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Phosphorylation of peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPAR gamma. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPAR gamma 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.

引用

页码：2361 / 2369

页数：9

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