The Potential Roles of Post-Translational Modifications of PPARγ in Treating Diabetes

Abstract

The number of patients with type 2 diabetes mellitus (T2DM), which is mainly characterized by insulin resistance and insulin secretion deficiency, has been soaring in recent years. Accompanied by many other metabolic syndromes, such as cardiovascular diseases, T2DM represents a big challenge to public health and economic development. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that is critical in regulating glucose and lipid metabolism, has been developed as a powerful drug target for T2DM, such as thiazolidinediones (TZDs). Despite thiazolidinediones (TZDs), a class of PPARγ agonists, having been proven to be potent insulin sensitizers, their use is restricted in the treatment of diabetes for their adverse effects. Post-translational modifications (PTMs) have shed light on the selective activation of PPARγ, which shows great potential to circumvent TZDs’ side effects while maintaining insulin sensitization. In this review, we will focus on the potential effects of PTMs of PPARγ on treating T2DM in terms of phosphorylation, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation, and S-nitrosylation. A better understanding of PTMs of PPARγ will help to design a new generation of safer compounds targeting PPARγ to treat type 2 diabetes.

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis—A Comprehensive One-Year Review

“…The capacity of H 2 S to regulate glucose uptake and energy metabolism might be harnessed for managing metabolic diseases, such as diabetes [ 107 , 108 ]. Modulating H 2 S levels could improve glucose homeostasis and insulin sensitivity, potentially serving as an adjunct to existing therapies [ 44 ].…”

“…H 2 S has gained unprecedented attention as a signaling molecule [ 96 ] in recent years. Its pivotal roles across animals and plants [ 107 , 108 ] in diverse cellular processes have triggered intensive exploration. Divergent as animals and plants may be in terms of physiology, metabolism, and anatomy, their pathways intersect when it comes to hydrogen sulfide’s indispensable roles.…”

The Deficits of Insulin Signal in Alzheimer’s Disease and the Mechanisms of Vanadium Compounds in Curing AD

“…PPARγ is a member of the nuclear hormone receptor family of ligand-inducible transcription factors, which plays a pivotal role in lipid and glucose homeostasis. The activity of PPARγ could be inhibited by CDK5 and MAPK [ 120 ] ( Figure 1 ). It was reported that the activation of PPARγ is involved in upregulating the level of the glucose-dependent insulinotropic polypeptide (GIP) receptor [ 121 ], GLUT4, and pyruvate carboxylase [ 122 , 123 ], which are correlated with insulin sensitization.…”

PPARγ in Atherosclerotic Endothelial Dysfunction: Regulatory Compounds and PTMs

“…With regard to the former, the bioactivity of PPARγ can be regulated by ligands that bind to peroxisome proliferator response elements (PPREs), the corepressor complex, and the co-activator complex through different domains [14,23]. PPARγ contains four different domains: ligand-independent activation function 1 (AF1), DNA-binding domain (DBD), ligand-binding domain (LBD), and activation function 2 (AF2) [14,24]. PPARγ can bind to PPREs of target genes through its DBD [14].…”

“…PTM patterns include acetylation, phosphorylation, ubiquitination, and small ubiquitin-related modifier (SUMOylation). In addition to the mRNA expression of PPARγ, increasing attention has been directed towards these PTMs [24][25][26][27]. In this review, we summarize the normal function versus dysfunction of ECs, with an emphasis on regulatory compounds and PTMs of PPARγ.…”