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

Citation data:

Diabetes, ISSN: 1939-327X, Vol: 65, Issue: 4, Page: 829-39

Publication Year:
2016
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Repository URL:
http://scholarworks.unist.ac.kr/handle/201301/18929
PMID:
26740599
DOI:
10.2337/db15-1382
Author(s):
Choi, Sun-Sil; Kim, Eun-Sun; Jung, Ji-Eun; Marciano, David P; Jo, Ala; Koo, Ja Young; Choi, Soo Youn; Yang, Yong Ryoul; Jang, Hyun-Jun; Kim, Eung-Kyun; Park, Jiyoung; Kwon, Hyug Moo; Lee, In Hee; Park, Seung Bum; Myung, Kyung-Jae; Suh, Pann-Ghill; Griffin, Patrick R; Choi, Jang Hyun Show More Hide
Publisher(s):
American Diabetes Association; AMER DIABETES ASSOC
Tags:
Medicine; ACTIVATED-RECEPTOR-GAMMA; IMATINIB-MESYLATE GLEEVEC; BEIGE FAT; IN-VITRO; LIGAND; PHOSPHORYLATION; GLUCOSE; OBESITY; THIAZOLIDINEDIONE; INFLAMMATION
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article description
Blocking phosphorylation of peroxisome proliferator-activated receptor (PPAR)γ at Ser(273) 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.