[ChoiJH]PPARg 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.

만성 골수성 백혈병에 대한 항암제로 사용되고 있던 gleevec이 핵내 수용체인 PPARg의 인산화를 선택적으로 억제함으로써 항당뇨 효과를 나타내었다. 특히 Gleevec이 기존의 PPARg target으로 하는 Thiazolidiediones(TZDs) 계열의 화합물이 가지는 부종, 골절, 심부전등의 부작용을 나타내지 않으면서 에너지 소비률을 증가시켜 체중 감소를 유도하는 것을 확인하였다. 따라서 이 연구 결과는비만과 당뇨를 동시에 치료 및 개선 시킬 수 있는 치료제 개발의 새로운 발향을 제시하였다.


Sun-Sil Choi, Eun-Sun Kim, Ji-Eun Jung, David P. Marciano, Ala Jo, Ja Young Koo, Soo Youn Choi, Yong Ryoul Yang, Hyun-Jun Jang, Eung-Kyun Kim, Jiyoung Park, Hyug Moo Kwon, In Hee Lee, Seung Bum Parke, Pann-Ghill Suh, Patrick R. Griffin, Jang Hyun Choi

Diabetes. 2016/01/16 on-line publish

impact factor : 8.474