Transcriptional control of PPARg by phosphorylation and anti-diabetic PPARg ligands
Date : April 23, 2015 16:30 ~
Speaker : Prof. Jang Hyun Choi(UNIST)
Location : Mogam Hall, Bldg.500
Thiazolidinedione (TZD) class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but TZDs can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe that gleevec, a well-known anti-cancer drug, binds tightly to PPARγ without the classical agonism and which blocks CDK5-mediated PPARγ phosphorylation. Surprisingly, gleevec treatment effectively ameliorated the inflammatory response both in vitro and in HFD-fed mice. Furthermore, gleevec treatment dramatically improved insulin sensitivity in HFD-fed mice without causing fluid retention and weight gain. Unexpectedly, treatment with gleevec in HFD-fed mice showed browning effects in white adipose tissues. Taken together, gleevec exhibited beneficial effects on glucose and lipid metabolism by blocking CDK5-mediated PPARγ phosphorylation, and these data indicate that gleevec could be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.
In the second chapter, I will propose the underlying molecular mechanisms that phosphorylation of PPARγ at Ser273 by CDK5 in adipose tissue stimulates insulin resistance. 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 programing mediated by the phosphorylation of PPARγ. Knock-down 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 (ASO) 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 programing, and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.
In the second chapter, I will propose the underlying molecular mechanisms that phosphorylation of PPARγ at Ser273 by CDK5 in adipose tissue stimulates insulin resistance. 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 programing mediated by the phosphorylation of PPARγ. Knock-down 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 (ASO) 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 programing, and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.
