BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice

• Published in: PloS one 2012-07, Vol.7 (7), p.e40056
• Main Authors: Wang, Long, Liu, Juan, Zhang, Aisen, Cheng, Peng, Zhang, Xiao, Lv, Shan, Wu, Lin, Yu, Jing, Di, Wenjuan, Zha, Juanmin, Kong, Xiaocen, Qi, Hanmei, Zhong, Yi, Ding, Guoxian
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11β-Hydroxysteroid dehydrogenase; 3T3-L1 Cells; Adipocytes; Adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Biology; Body weight; Body Weight - drug effects; Cardiovascular disease; Chemokine CCL2 - biosynthesis; Dehydrogenase; Dehydrogenases; Diabetes; Diet; Diet - adverse effects; Enzyme Inhibitors - pharmacology; Fatty acids; Fuel consumption; Gene expression; Glucocorticoids; Glucocorticoids - metabolism; Glucose tolerance; High fat diet; Homeostasis; Hospitals; Hydroxysteroids; Hypertension; Infiltration; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - enzymology; Inflammation - pathology; Inflammation Mediators - metabolism; Inhibition; Inhibitors; Insulin; Insulin Resistance; Interleukin 6; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Medicine; Metabolic disorders; Metabolic syndrome; Metastases; Mice; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; mRNA; Obesity; Obesity - chemically induced; Obesity - drug therapy; Obesity - enzymology; Obesity - pathology; Pharmaceutical industry; Pharmacology; Piperazines - pharmacology; Preventive medicine; Ribonucleic acid; RNA; RNA-mediated interference; Rodents; Sulfonamides - pharmacology; Therapeutic applications; Thiazoles - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis; Tumor necrosis factor-α; Weight control
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040056

Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11β-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11β-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11β-HSD1 may be a very promising therapeutic target for obesity and associated disease.