Advances on PPARγ Research in the Emerging Era of Precision Medicine

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor. It regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are potent insulin sensitizers that function by activating PPARs, with a high specificity for PPARγ. Due to their ability to preserve pancreatic beta cell function and reduce insulin resistance, TZDs have become one of the most prescribed classes of medications for type 2 diabetes (T2D) since their approval by the US Food and Drug Administration (FDA) and initial use in 1997. Objective: However, adverse effects, including weight gain, bone loss, fluid retention, congestive heart failure, and risk to bladder cancer, have weakened the benefits of TZDs in T2D therapies. Therefore, there is an urgent need to have a deeper understanding of regulatory mechanisms of PPARγ expression and activity so that novel classes of PPARγ-modulating therapeutics with fewer or weaker side effects can be developed. Conclusion: This article systematically reviews PPARγ's mechanisms of action and multilayer regulations. In addition, novel classes of therapeutics modulating PPARγ and new direction of research on genetic variants that affect PPARγ function and antidiabetic drug response are highlighted, which sheds light on PPARγ as a promising target for developing safer and precision medicine based therapeutic strategies.