Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.
Highlights
Insulin resistance is the key pathophysiologic abnormality of many metabolic diseases such as type 2 diabetes mellitus, obesity, dyslipidemia, and cardiovascular diseases[1]
TZDs demonstrated a preventive role for recurrent ischemic stroke in several clinical trials[4] and for restenosis after percutaneous coronary intervention (PCI)[5,6,7]
Later studies revealed that rosiglitazone did not increase the risk of heart attack and the US Food and Drug Administration (FDA) removed the warning labels from rosiglitazone-containing drugs regarding the issue of increasing heart attack in 2013, rosiglitazone’s cardiovascular safety issue alongside the above-mentioned adverse effects still lead to many physicians hesitating to prescribe TZDs in their clinical practice
Summary
Insulin resistance is the key pathophysiologic abnormality of many metabolic diseases such as type 2 diabetes mellitus, obesity, dyslipidemia, and cardiovascular diseases[1]. Rosiglitazone significantly increased endothelial cell migration and vascular leakage in an animal study with increased VEGF expression and suppressed tight junction proteins, which caused instability of the endothelial membrane[41] This result could be related to vascular permeability, peripheral edema, and congestive heart failure associated with the use of TZDs, contrary to their beneficial effect on vascular cells. SR1664 and similar non-agonist PPARγ ligands were developed for blocking cdk5-mediated phosphorylation and showed improved insulin sensitivity in high-fat diet-fed mice without causing side effects such as fluid retention and weight gain[43,50]. IVA 337 is a potent and well-balanced pan PPAR agonist which showed promising results in vitro and in vivo and is expected to be used to treat patients with metabolic syndrome and non-alcoholic steatohepatitis[76]
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