A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation

被引：22

作者：

Park, Ji Seon ^{[1
]}

Bae, Su Jung ^{[1
,2
,3
]}

Choi, Sik-Won ^{[4
]}

Son, You Hwa ^{[4
]}

Park, Sung Bum ^{[1
,5
]}

Dal Rhee, Sang ^{[1
]}

Kim, Hee Youn ^{[1
]}

Jung, Won Hoon ^{[1
]}

Kang, Seung Kyu ^{[1
]}

Ahn, Jin Hee ^{[1
]}

Kim, Seong Hwan ^{[4
]}

Kim, Ki Young ^{[1
,6
]}

机构：

[1] Korea Res Inst Chem Technol, Div Drug Discovery Res, Taejon 305600, South Korea

[2] Ewha Womans Univ, Div Life & Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea

[3] Ewha Womans Univ, Ctr Cell Signaling & Drug Discovery Res, Coll Pharm, Seoul 120750, South Korea

[4] Korea Res Inst Chem Technol, Pharmacol Res Ctr, Lab Translat Therapeut, Taejon 305600, South Korea

[5] Chungnam Natl Univ, Dept Toxicol, Coll Pharm, Taejon 305764, South Korea

[6] Univ Sci & Technol, Dept Med & Pharmaceut Chem, Taejon 305333, South Korea

来源：

JOURNAL OF MOLECULAR ENDOCRINOLOGY | 2014年 / 52卷 / 02期

关键词：

adipose tissue; diabetes II; obesity; osteoporosis; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; GLUCOCORTICOID-INDUCED OSTEOPOROSIS; INSULIN-RESISTANCE; GLUCOSE-TRANSPORTER; METABOLIC SYNDROME; VISCERAL OBESITY; C2C12; CELLS; MICE; BONE; EXPRESSION;

D O I：

10.1530/JME-13-0177

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Selective inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11b-HSD1 inhibitor. Cellular 11b-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50 mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The in vitro anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The in vitro anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the in vivo glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11b-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.

引用

页码：191 / 202

页数：12

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