title: PPARγ Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Sun-Sil
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Jung
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL.
authors.forename: David P
authors.initials: DP
authors.lastname: Marciano
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea.
authors.forename: Ala
authors.initials: A
authors.lastname: Jo
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Koo
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Eung-Kyun
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Hyug Moo
authors.initials: HM
authors.lastname: Kwon
authors.affiliation: Department of Medical Chemistry, Hyundai Pharm Co., Ltd., Suwon, Korea.
authors.forename: In Hee
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea Department of Biophysics and Chemical Biology/N-Bio institute, Seoul National University, Seoul, Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: Center for Genomic Integrity, Institute for Basic Science, Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Kyung-Jae
authors.initials: KJ
authors.lastname: Myung
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea janghchoi@unist.ac.kr.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000502:physiology; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000037:antagonists & inhibitors*
chemical_list: D047495:PPAR gamma; D000068877:Imatinib Mesylate