PPAR gamma Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue

Abstract

Blocking phosphorylation of peroxisome proliferator-activated receptor (PPAR)gamma at Ser(273) is one of the key mechanisms for antidiabetes drugs to target PPAR gamma. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5-mediated PPAR gamma phosphorylation devoid of classical agonism as a PPAR gamma antagonist ligand. In high fat-fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPAR gamma-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 and energy expenditure. Taken together, the results indicate that Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPAR gamma phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.