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

ABSTRACT: Blocking phosphorylation of peroxisome proliferator-activated receptor (PPAR)? at Ser(273) is one of the key mechanisms for antidiabetes drugs to target PPAR?. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5-mediated PPAR? phosphorylation devoid of classical agonism as a PPAR? antagonist ligand. In high fat-fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPAR?-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? phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes.

SUBMITTER: Choi SS 

PROVIDER: S-EPMC5314706 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature