Re-highlighting the action of PPARγ in treating metabolic diseases

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.

Safflower yellow improves insulin sensitivity in high‐fat diet‐induced obese mice by promoting peroxisome proliferator‐activated receptor‐γ2 expression in subcutaneous adipose tissue

“…Peroxisome proliferator-activated receptor-c (PPARc) is a critical transcription factor in regulating adipogenesis in adipose tissues 4 . PPARc plays important roles in the regulation of lipids, and glucose metabolism and insulin sensitivity [5][6][7] , and thus is associated with the control of obesity and related diseases 7 .…”

“…PPARc1 is widely expressed, whereas PPARc2 is predominately expressed in adipose tissue 5,6 . PPARc is the molecular target of thiazolidinediones (TZDs), which have been used in treating diabetes mellitus for two decades 4 . TZDs have many beneficial effects by improving insulin sensitivity 4 .…”

“…PPARc is the molecular target of thiazolidinediones (TZDs), which have been used in treating diabetes mellitus for two decades 4 . TZDs have many beneficial effects by improving insulin sensitivity 4 . However, there are many side-effects of TZDs, including bodyweight gain, fluid retention and cardiovascular dysfunction 8,9 .…”

PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPARγ at Ser273

“…Post-translational modifications of PPARγ orchestrate various functions of the protein [18,25,26]. In obesity, phosphorylation of PPARγ on the Ser273 residue by CDK5 leads to dysregulation of a specific gene set [28].…”

“…The transcriptional activity of PPARγ is activated by its ligands, which include thiazolidinediones (TZDs) [24]. In addition to its ligands, recent studies demonstrated that post-translational modifications (PTMs) of PPARγ, including phosphorylation, small ubiquitin-like modifier (SUMO)-ylation, acetylation, and ubiquitination, are major regulatory mechanisms of PPARγ activation and PPARγ-mediated gene transcription [18,25,26]. Of these, phosphorylation is thought to be a crucial regulator of the transcriptional regulatory activity of PPARγ.…”