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

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.

• Authors: 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
• Journal: Endocrine journal (Endocr J) Vol. 58 Issue 3 Pg. 199-209 ( 2011) ISSN: 1348-4540 [Electronic] Japan
• PMID: 21325744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide
• Adiponectin
• Dietary Fats
• Enzyme Inhibitors
• Piperazines
• Sulfonamides
• Thiazoles
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Nicotinamide Phosphoribosyltransferase

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• Adipocytes (pathology)
• Adiponectin (metabolism)
• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Body Weight (drug effects)
• Dietary Fats (adverse effects)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Glucose Intolerance (drug therapy)
• Injections, Subcutaneous
• Male
• Mice
• Mice, Inbred C57BL
• Nicotinamide Phosphoribosyltransferase (metabolism)
• Obesity (etiology, prevention & control)
• Piperazines (administration & dosage, pharmacology, therapeutic use)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)
• Thiazoles (administration & dosage, pharmacology, therapeutic use)