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Journal of Biochemistry Advance Access originally published online on October 26, 2007
Journal of Biochemistry 2007 142(5):639-645; doi:10.1093/jb/mvm172
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© 2007 The Japanese Biochemical Society

Gliclazide Inhibits Proliferation but Stimulates Differentiation of White and Brown Adipocytes

Norihiko Nakano1,*,{dagger}, Nobuko Miyazawa1, Takuya Sakurai1, Takako Kizaki1, Kiyoko Kimoto1, Kazuto Takahashi2, Hitoshi Ishida2, Motoko Takahashi3, Kenji Suzuki4 and Hideki Ohno1

1Department of Molecular Predictive Medicine and Sport Science; 2Third Department of Internal Medicine, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611; 3Department of Biochemistry, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku, Sapporo 060-8556; and 4Laboratory of Molecular Medicinal Sciences, Department of Bioscience and Bioinformatics, College of Information Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan

{dagger}To whom correspondence should be addressed. Tel: +81-72-621-5087, Fax: +81-72-627-7882, E-mail: n-nakano{at}aino.ac.jp

Received July 8, 2007; Accepted August 30, 2007


  Abstract

Gliclazide, a second-generation sulfonylurea, has anti-oxidant properties as well as hypoglycemic activities. In the present study, we investigated whether gliclazide affected proliferation and/or differentiation of HW white and HB2 brown adipocyte cell lines. Gliclazide inhibited proliferation of HW and HB2 cells in the medium containing fetal calf serum or epidermal growth factor (EGF). Gliclazide inhibited phosphorylation of EGF receptor and of extracellular signal-regulated kinase (ERK) 1/2 stimulated by EGF. Gliclazide increased lipid accumulation and peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) expression in the early stage of differentiation of adipocytes. A KATP channel activator, diazoxide, did not inhibit the increase of lipid accumulation by gliclazide. Furthermore, gliclazide inhibited the DNA-binding activity of PPAR{gamma} in mature adipocytes. On the other hand, glibenclamide, other sulfonylurea, did not show these effects. These results indicate gliclazide inhibits proliferation and stimulates differentiation of adipocytes via down-regulation of the EGFR signalling. Gliclazide may have preventive and therapeutic effects on obesity, as well as on type 2 diabetes.

Key Words: adipocyte, EGF, gliclazide, PPAR{gamma}, proliferation and differentiation

Abbreviations: DEX, dexamethasone; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; FCS, fetal calf serum; IBMX, 3-isobuthyl-1-methylxanthine; PPAR, peroxisome proliferator-activated receptor; PS, penicillin/streptomycin sulfate; RXR, retinoid X receptor; SUR, sulfonylurea receptor; TNF-{alpha}, tumor necrosis factor-{alpha}

*Present address: Aino Institute of Regeneration and Rehabilitation, 4-5-11 Higashiohda, Ibaraki, Osaka 567-0012, Japan.


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