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Adipose Tissue-Targeted 11β-hydroxysteroid Dehydrogenase Type 1 Inhibitor Protects Against Diet-Induced Obesity

Adipose Tissue-Targeted 11β-hydroxysteroid Dehydrogenase Type 1 Inhibitor Protects Against Diet-Induced Obesity

Juan Liu, Long Wang, Aisen Zhang, Wenjuan Di, Xiao Zhang, Lin Wu, Jing Yu, Juanmin Zha, Shan Lv, Peng Cheng, Miao Hu, Yujie Li, Hanmei Qi, Guoxian Ding, Yi Zhong

Endocr J. 2011;58(3):199-209.

PMID: 21325744

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP376640414	BVT.2733		376640-41-4	Price

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