PPARγ signaling and emerging opportunities for improved therapeutics

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARγ are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPARγ signaling and to develop safer and more effective PPARγ-directed therapeutics. In addition to PPARγ itself, many PPARγ ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPARγ responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPARγ genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPARγ co-activator-1α, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPARγ-dependent transcription. Therefore in endothelium, GPR40 and PPARγ function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPARγ. Thus the role of GPR40 in PPARγ signaling may have important implications for drug development. Ligands that strongly activate PPARγ, but do not bind to or activate GPR40 may be safer than currently approved PPARγ agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPARγ, but not ERK1/2, avoiding its harmful effects on PPARγ signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation

“…To verify the known insulin-sensitizing effect of thiazolidinediones, we assessed the effects of rosiglitazone treatment on body weight and fasting or challenged blood glucose levels in the mice. As given in S4 Fig, we observed a significant increase in body weight upon rosiglitazone treatment (S4A Fig), which is a well-known side effect of PPARγ agonists [40]. In line, the insulin-sensitizing effect of rosiglitazone was reflected in reduced fasting blood glucose levels (S4B Fig) and an improved insulin sensitivity after oral glucose administration (S4C Fig).…”

“…Here it is tempting to argue in favor of the well-known insulin-sensitizing effects of thiazolidinedones [40], which might preferentially account for the improved tissue repair in ob/ob mice rather than the attenuated inflammatory conditions at the wound site. However, this notion actually does not reflect the actual conditions at impaired wound sites.…”

Peroxisome proliferator‐activated receptor γ plays dual roles on experimental periodontitis in rats

“…During the pathogenesis of periodontitis, the mechanism for the absorption of alveolar bone involves in bone matrix damaged and bone cells invaded by bacteria, osteoclasts activation induced by inflammatory mediators, and the inhibition of bone formation (Henderson & Nair, ). RGZ can increase the sensitivity of insulin and was used as a treatment for type 2 diabetes (Wang, Dougherty, & Danner, ). Previous studies showed that the long‐term use of RGZ caused reduction in bone mineral density (Lecka‐Czernik, ) and elevated bone fracture rate (Choi, Park, & Choi, ), and proposed an underlying mechanism that RGZ promoted the activation of osteoclasts and inhibit osteoblast formation (Wan, ).…”

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

“…Furthermore, intracellular RHAMM protein isoforms complex with, sustain activity and regulate subcellular targeting of the MEK1/ERK1,2 complexes that affect adipogenesis [38]. Intracellular RHAMM also partners with anti-adipogenic proteins such as the ERK1,2 target protein ANKRYD26[39, 78], which results in suppression of the activation and expression of master adipogenic transcription factors such as PPARγ[79]. …”