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

Abstract

BACKGROUND:

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.

METHODOLOGY/PRINCIPAL FINDINGS:

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.

CONCLUSIONS/SIGNIFICANCE:

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.

• Authors: Long Wang, Juan Liu, Aisen Zhang, Peng Cheng, Xiao Zhang, Shan Lv, Lin Wu, Jing Yu, Wenjuan Di, Juanmin Zha, Xiaocen Kong, Hanmei Qi, Yi Zhong, Guoxian Ding
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e40056 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22768329 (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
• Ccl2 protein, mouse
• Chemokine CCL2
• Enzyme Inhibitors
• Glucocorticoids
• Inflammation Mediators
• Piperazines
• Sulfonamides
• Thiazoles
• Tumor Necrosis Factor-alpha
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, metabolism)
• 3T3-L1 Cells
• Adipose Tissue (metabolism, pathology)
• Animals
• Body Weight (drug effects)
• Chemokine CCL2 (biosynthesis)
• Diet (adverse effects)
• Enzyme Inhibitors (pharmacology)
• Glucocorticoids (metabolism)
• Inflammation (chemically induced, drug therapy, enzymology, pathology)
• Inflammation Mediators (metabolism)
• Insulin Resistance
• Macrophages (metabolism, pathology)
• Male
• Mice
• Obesity (chemically induced, drug therapy, enzymology, pathology)
• Piperazines (pharmacology)
• Sulfonamides (pharmacology)
• Thiazoles (pharmacology)
• Tumor Necrosis Factor-alpha (biosynthesis)