PPARγ antagonist Gleevec improves insulin sensitivity and promotes the browning of white adipose tissue

Blocking phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 is one of the key mechanisms for anti-diabetic drugs to target PPARγ. Using high throughput phosphorylation screening, we here describe that Gleevec blocks CDK5-mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand. In high fat-fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPARγ-targeting drugs. Furthermore, Gleevec reduces lipogenic and gluconeogenic gene expression in liver and ameliorates inflammation in adipose tissues. Interestingly, Gleevec increases browning of white adipose tissue (WAT) and energy expenditure. Taken together, Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPARγ phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes.