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: Sooho Lee, Woo Kyeom Yang, Ji Ho Song, Young Min Ra, Jin-Hyun Jeong, Wonchae Choe, Insug Kang, Sung-Soo Kim, Joohun Ha
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 7 Pg. 965-76 (Apr 01 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23337568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
• 3-hydroxychromone
• Aminophenols
• Anti-Obesity Agents
• Chromones
• Maleimides
• Thiazoles
• beta Catenin
• Glycogen Synthase Kinase 3
• Lithium Chloride

Topics

• 3T3-L1 Cells
• Adipocytes (cytology, drug effects, metabolism)
• Adipogenesis
• Adiposity (drug effects)
• Aminophenols (pharmacology)
• Animals
• Anti-Obesity Agents (chemistry, pharmacology)
• Body Weight (drug effects)
• Cell Differentiation
• Chromones (chemistry, pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• HEK293 Cells
• Hep G2 Cells
• Humans
• Lipid Metabolism (drug effects)
• Lithium Chloride (pharmacology)
• Male
• Maleimides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Obesity (drug therapy, pathology, physiopathology)
• Protein Stability
• Thiazoles (chemistry, pharmacology)
• beta Catenin (metabolism)