LAB of  Diabetes and Metabolism 

 1) Regulation of PPARg phosphorylation by specific modulator in adipose tissue

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♦ Adipose tissue is the center of the metabolic diseases. Excessive body fat defines obesity and leads to insulin resistance, dyslipidemia, type 2 diabetes, certain cancers and cardiovascular disease. Understanding the molecular pathways that link adipose tissue biology to this staggering array of pathologies is of paramount scientific and medical importance.

   Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors which is highly expressed in adipose tissue and regulates diverse biological functions, including adipocyte differentiation, lipid and glucose metabolism, and inflammation. Our lab recently found that PPARγ was phosphorylated at a specific site, Ser273, by cyclin-dependent kinase 5 (CDK5) in obese and diabetic mice. The phosphorylation of PPARγ at this site did not globally alter its transcriptional activity but dysregulated a specific set of genes whose expression was altered in obesity and diabetes (Nature 2010; Nature 2011). Furthermore, we also found this phosphorylated PPARγ recruits specific co-regulator, Thrap3, which resulted in regulation of diabetic gene programing and insulin resistance (Genes & Development 2014).

  Our lab is currently trying to characterize the functional roles of Thrap3 in vitro and in vivo and understand the mechanism of Thrap3 to regulate systemic glucose and lipid homeostasis, which will help us to understand the development of insulin resistance and may provide opportunities for developing new therapeutics for type 2 diabetes.
 

 2) Anti-diabetic drugs via specific inhibition of PPARg S273 phosphorylation

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♦ As the prevalence of obesity has exploded over the last several decades, associated metabolic disorders, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular diseases, have also increased dramatically. As PPARγ agonists, thiazolidinediones (TZDs), which include pioglitazone, represent synthetic insulin-sensitizing drugs that have been widely prescribed for the treatment of type 2 diabetes. However, the use of TZDs, classical full agonist, is associated with unwanted side effects, including weight gain, fluid retention, bone fracture, cardiovascular disease, and bladder cancer. Thus, the U.S. Food and Drug Administration (FDA) recently restricted the use of one TZD, Avandia, for the treatment of type 2 diabetes.

  Recent studies have shown that the insulin-sensitizing effects of PPARγ ligands are not dependent on classical agonism but, rather, are a consequence of ligand-dependent inhibition of phosphorylation of PPARγ at Ser273 (pS273). More specifically, nonagonist PPARγ ligands, such as SR1664 and UHC1, have illustrated glucose-lowering effects similar to those of TZDs while lacking the commonly observed side effects (Nature 2011, Journal of Biological Chemistry 2014, PNAS 2018). These studies have allowed us the opportunity to find a potential compound for the treatment of type 2 diabetes. Thus, we aimed to discover compounds that block pS273 and lack classical agonism with high binding affinity to PPARγ (Angewante Chemie-International Edition 2014, Chemical Science 2016). Drug repositioning is the application of known drugs and compounds to new indications, which can save time and costs because they have already been tested in humans and detailed information is available on their pharmacology, formulation, and potential toxicity.

  Thus, we screened PPARγ ligands that block pS273 with an FDA-approved drug library, and Gleevec, a well-known anticancer drug, was determined to fit these criteria (Diabetes 2016). At the same time, we are also trying to screen PPARγ ligand using natural compounds and novel synthetic compounds. These effects facilitate the development of new concept for PPARγ-based anti-diabetic drugs.