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