Dosing PPARγ Activation With Light Using Fast Relaxing Photoswitches.

The transcription factor PPARγ regulates glucose and lipid homeostasis, and its activation, e.g., with glitazones, has antidiabetic, insulin-sensitizing activity, but also adverse effects which possibly arise from overstimulation. Here we developed a novel high-precision tool to enable light-dosed PPARγ activation. Structure-guided incorporation of a photoswitchable diazene motif into a PPARγ ligand and molecular fine-tuning provided potent, light-activated PPARγ agonists with millisecond to multiple-hour half-lives, suitable for biological research applications. Phenotypic effects of light-dosed PPARγ activation in an in vitro model of adipogenesis suggested time-dependent importance of the receptor in adipocyte development and illustrated the unprecedented precision of controlling PPARγ activity with light-activated chemical tools.