title: Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3.
abstract: Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment.
authors: Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Sooho
authors: S
authors: Lee
authors: Woo Kyeom
authors: WK
authors: Yang
authors: Ji Ho
authors: JH
authors: Song
authors: Young Min
authors: YM
authors: Ra
authors: Jin-Hyun
authors: JH
authors: Jeong
authors: Wonchae
authors: W
authors: Choe
authors: Insug
authors: I
authors: Kang
authors: Sung-Soo
authors: SS
authors: Kim
authors: Joohun
authors: J
authors: Ha
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis; D050154:Adiposity / Q000187:drug effects; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D055550:Protein Stability; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; C479534:3-hydroxychromone; D000627:Aminophenols; D019440:Anti-Obesity Agents; D002867:Chromones; D008301:Maleimides; D013844:Thiazoles; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride