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

作者：Park Ji Seon; Bae Su Jung; Choi Sik Won; Son You Hwa; Park Sung Bum; Dal Rhee Sang; Kim Hee Youn; Jung Won Hoon; Kang Seung Kyu; Ahn Jin Hee; Kim Seong Hwan; Kim Ki Young^*

来源：Journal of Molecular Endocrinology, 2014, 52(2): 191-202.

DOI：10.1530/JME-13-0177

• adipose tissue
• diabetes II
• obesity
• osteoporosis

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.

• 出版日期2014-4