PPARγ signaling and metabolism: the good, the bad and the future

Abstract

Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.

Figure 1

PPARγ has multiple roles in adipose tissue. HFD, ligands or TZDs (1) activate PPARγ-RXR functional heterodimers (2) and maintain metabolic homeostasis through direct regulation of genes harboring PPAR response elements (PPREs) involved in adipocyte differentiation, lipid metabolism and glucose homeostasis, as well as the expression of adipose secreted factors that act as transducers for PPARγ (3). C/EBPα, CCAAT/enhancer-binding protein α; STAT1, STAT5A and STAT5B, signal transducer and activator of transcription 1, 5A and 5B, respectively; aP2, fatty acid binding protein 2; ACBP, acyl-CoA–binding protein; LPL, lipoprotein lipase; CD36, cluster of differentiation 36; PEPCK, phosphoenolpyruvate carboxykinase; ACS, acyl-CoA synthetase; GyK, glycerol kinase; Glut4, glucose transporter 4; PI3K, phosphoinositide 3 kinase; IRS-1 and IRS-2, insulin receptor substrate 1 and 2, respectively.

Figure 2

Known effects of PPARγ activation. Activation of PPARγ results in beneficial effects (green arrows) as well as adverse side effects (red arrows).

Figure 3

Post-translational modifications of PPARγ. Post-translational modifications of PPARγ influence both its transcriptional activity and its protein stability in a cell- and context-dependent manner. Ac, acetylation; P, phosphorylation; Cdk9/Cdk7, Cyclin-dependent kinases 9 and 7.