Adipose tissue-targeted 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity

• Published in: Endocrine Journal 2011, Vol.58(3), pp.199-209
• Main Authors: Liu, Juan, Wang, Long, Zhang, Aisen, Di, Wenjuan, Zhang, Xiao, Wu, Lin, Yu, Jing, Zha, Juanmin, Lv, Shan, Cheng, Peng, Hu, Miao, Li, Yujie, Qi, Hanmei, Ding, Guoxian, Zhong, Yi
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11β-hydroxysteroid dehydrogenase type 1; Adipocytes - pathology; Adiponectin - metabolism; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Blood glucose; Body Weight - drug effects; Dietary Fats - adverse effects; Disease Models, Animal; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glucose Intolerance - drug therapy; Injections, Subcutaneous; Male; Metabolic syndrome; Mice; Mice, Inbred C57BL; Nicotinamide Phosphoribosyltransferase - metabolism; Obesity - etiology; Obesity - prevention & control; Piperazines - administration & dosage; Piperazines - pharmacology; Piperazines - therapeutic use; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Thiazoles - administration & dosage; Thiazoles - pharmacology; Thiazoles - therapeutic use
• ISSN: 0918-8959; 1348-4540
• DOI: 10.1507/endocrj.K10E-318

Current pharmacological treatments for obesity and metabolic syndrome have various limitations. Recently, adipose tissue 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of obesity and metabolic syndrome. Nevertheless, there is no adipose tissue-targeted 11β-HSD1 inhibitor available now. We sought to develop a new 11β-HSD1 pharmacological inhibitor that homes specifically to the white adipose tissue and aimed to investigate whether adipose tissue-targeted 11β-HSD1 inhibitor might decrease body weight gain and improve glucose tolerance in diet-induced obesity mice. BVT.2733, an 11β-HSD1 selective inhibitor was connected with a peptide CKGGRAKDC that homes to white fat vasculature. CKGGRAKDC-BVT.2733 (T-BVT) or an equimolar mixture of CKGGRAKDC and BVT.2733 (NT-BVT) was given to diet-induced obesity mice for two weeks through subcutaneous injection. T-BVT decreased body weight gain, improved glucose tolerance and decreased adipocyte size compared with vehicle treated mice. In adipose tissue T-BVT administration significantly increased adiponectin, vaspin mRNA levels; In liver T-BVT administration decreased the mRNA level of phosphoenolpyruvate carboxykinase (PEPCK), increased the mRNA levels of mitochondrial carnitine palmi-toyltransferase-I (mCPT-I) and peroxisome proliferator-activated receptorα(PPARα). No significant differences in adipocyte size and hepatic gene expression were observed after treatment with NT-BVT compared with vehicle treated mice, though NT-BVT also decreased body weight gain, improved glucose tolerance, and increased uncoupling protein-2 (UCP-2) mRNA levels in muscle. These results suggest that an adipose tissue-targeted pharmacological inhibitor of 11β-HSD1 may prove to be a new approach for the treatment of obesity and metabolic syndrome.