Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3

Sooho Lee, Woo Kyeom Yang, Ji Ho Song, Young Min Ra, Jin-Hyun Jeong, Wonchae Choe, Insug Kang, Sung Soo Kim, Joohun Ha

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)965-976
Number of pages12
JournalBiochemical Pharmacology
Volume85
Issue number7
DOIs
Publication statusPublished - 2013 Apr 1

Fingerprint

Glycogen Synthase Kinase 3
Obesity
Derivatives
Molecules
Catenins
Bearings (structural)
Phosphotransferases
3-hydroxychromone
Small Molecule Libraries
Obese Mice
Glycogen Synthase
HEK293 Cells
Liver
Adiposity
Nutrition
Medical problems
Dyslipidemias
Lipid Metabolism
Adipocytes
Type 2 Diabetes Mellitus

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Lee, Sooho ; Yang, Woo Kyeom ; Song, Ji Ho ; Ra, Young Min ; Jeong, Jin-Hyun ; Choe, Wonchae ; Kang, Insug ; Kim, Sung Soo ; Ha, Joohun. / Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. In: Biochemical Pharmacology. 2013 ; Vol. 85, No. 7. pp. 965-976.
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Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. / Lee, Sooho; Yang, Woo Kyeom; Song, Ji Ho; Ra, Young Min; Jeong, Jin-Hyun; Choe, Wonchae; Kang, Insug; Kim, Sung Soo; Ha, Joohun.

In: Biochemical Pharmacology, Vol. 85, No. 7, 01.04.2013, p. 965-976.

Research output: Contribution to journalArticle

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