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

ABSTRACT: 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 adip

SUBMITTER: Wu D 

PROVIDER: S-EPMC12746064 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature