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

Abstract

Thiazolidinediones (TZDs), which act through the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ), are a widely prescribed class of drugs for type 2 diabetes; however, their use has been challenged by a number of side effects. Here the authors outline recent advances in our understanding of the modulation of the PPARγ pathway in metabolism and discuss how these insights might be used to explain the adverse side effects of TZD therapy and develop a new generation of safer PPARγ-targeting drugs. 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.