Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety.

The nuclear receptor PPARγ is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPARγ agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPARγ acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPARγ acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPARγ acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 à resolution reveals a unique binding mode of TPMD molecules to the PPARγ ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPARγ acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.