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BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in
Long Wang1, Juan Liu, Aisen Zhang
1Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China.
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.
Insights
Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with BVT.2733 reduces body weight and adipose tissue inflammation in obese mice. This suggests 11β-HSD1 is a promising therapeutic target for obesity and metabolic syndrome.
Area of Science:
- Endocrinology
- Metabolic Syndrome Research
- Obesity Therapeutics
Background:
- 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition is a potential therapeutic strategy for obesity and metabolic syndrome.
- Glucocorticoid action suppression by 11β-HSD1 inhibitors necessitates investigation into their effects on adipose tissue inflammation.
Purpose of the Study:
- To investigate the impact of BVT.2733, a selective 11β-HSD1 inhibitor, on pro-inflammatory mediators and macrophage infiltration in adipose tissue.
- To evaluate the therapeutic potential of 11β-HSD1 inhibition in diet-induced obesity models.
Main Methods:
- C57BL/6J mice were fed high-fat diets (HFD) and treated with BVT.2733 or vehicle for four weeks.
- Gene expression of inflammatory mediators (MCP-1, TNF-α, IL-6) and macrophage infiltration were assessed in adipose tissue.
- In vitro studies utilized cultured macrophages and preadipocytes to examine the effects of 11β-HSD1 inhibition.
Main Results:
- BVT.2733 treatment led to decreased body weight, improved glucose tolerance, and enhanced insulin sensitivity in HFD mice.
- Adipose tissue in BVT.2733-treated mice showed reduced expression of inflammation-related genes (MCP-1, TNF-α) and decreased macrophage infiltration.
- Pharmacological and RNA interference-mediated inhibition of 11β-HSD1 reduced MCP-1 and IL-6 mRNA levels in vitro.
Conclusions:
- BVT.2733 treatment effectively reduces body weight, improves metabolic homeostasis, and suppresses adipose tissue inflammation in diet-induced obese mice.
- These findings highlight 11β-HSD1 as a promising therapeutic target for managing obesity and related metabolic disorders.
- Targeting 11β-HSD1 offers a potential strategy for combating inflammation associated with obesity.
