No abstract

No abstract

Background: PPAR␥ ligands can be used in numerous metabolic syndromes. Results: A novel non-agonist PPAR␥ ligand, UHC1 exhibited great beneficial effects on glucose metabolism and anti-inflammatory response. Conclusion: UHC1 shows anti-diabetic action by blocking CDK5-mediated PPAR␥ phosphorylation. Significance: UHC1 can be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.

No abstract

Blocking phosphorylation of peroxisome proliferator–activated receptor (PPAR)γ at Ser273 is one of the key mechanisms for antidiabetes drugs to target PPARγ. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5–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 and energy expenditure. Taken together, the results indicate that 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.