11β-hydroxysteroid Dehydrogenase Type1Inhibitor, Attenuates Obesity And Inflammation In Diet-induced Obese Mice

Excessive glucocorticoid exposure or exogenous administration results inincreased central adiposity and the metabolic syndrome. The dysregulation ofcortisol metabolism associates with adiposity and the metabolic syndrome.11β-hydroxysteroid dehydrogenase type1(11β-HSD1) represents an intracellularamplifer of active glucocorticoid, may convert inactive glucocorticoid to activeglucocorticoid. Recently, several transgenic mice models have supported thatadipose tissue11β-HSD1plays a key role in the pathogenesis of visceral obesity andthe metabolic syndrome, adipose tissue11β-HSD1has been proposed as a noveltherapeutic target for the treatment of obesity and metabolic syndrome. Nevertheless,there is no adipose tissue-targeted11β-HSD1inhibitor available now. We sought todevelop a new11β-HSD1pharmacological inhibitor that homes specifically to thewhite adipose tissue and aimed to investigate whether and how adiposetissue-targeted11β-HSD1inhibitor decreases body weight gain and improvesglucose tolerance in diet-induced obesity (DIO) mice. We found that T-BVTmediated adipose tissue-targeted11β-HSD-1Inhibition not only improved theexpression of adipokine but also improved the glucose and fat metabolism of liver.On the other hand, the profound effects of glucocorticoid on the immune systemhave underpinned its widespread use as therapeutic agent for inflammatory diseases.The magnified glucocorticoid action caused by11β-HSD1might function as animportant regulator at the interface of inflammation and obesity. Furthermore,obesity is associated with a chronic low-grade inflammation state, an important risk factor in cardiovascular disease. Therefore, there is an urgent requirement toestablish the effects of11β-HSD1inhibitor on the inflammation of adipose tissue.Based on the results described above, we further examined the effect of BVT.2733on inflammation-related gene expression and macrophage infiltration in adiposetissue in diet-induced obese mice. Finally,our cell-based and animal results revealedthat11β-HSD1is an important regulator at the interface of obesity and inflammation,and the inhibition of11β-HSD1by BVT.2733could prevent the development ofobesity and reduce the inflammation of adipose tissue both in vivo and in vitro. Ourstudy suggests that11β-HSD1maybe be a promising target of obesity-associateddiseases. Our research was divided into two parts.Part I: Adipose tissue-targeted11β-hydroxysteroid dehydrogenase type1inhibitor protects against diet-induced obesityPart II: BVT.2733, a selective11β-hydroxysteroid dehydrogenase type1inhibitor, attenuates obesity and inflammation in diet-induced obese micePart I: Adipose tissue-targeted11β-hydroxysteroiddehydrogenase type1inhibitor protects against diet-inducedobesityObjective: Current pharmacological treatments for obesity and metabolic syndromehave various limitations. Recently, adipose tissue11β-hydroxysteroiddehydrogenase type1(11β-HSD1) has been proposed as a novel therapeutic targetfor the treatment of obesity and metabolic syndrome. Nevertheless, there is noadipose tissue-targeted11β-HSD1inhibitor available now. We sought to develop anew11β-HSD1pharmacological inhibitor that homes specifically to the white adipose tissue and aimed to investigate whether adipose tissue-targeted11β-HSD1inhibitor might decrease body weight gain and improve glucose tolerance indiet-induced obesity mice.Methods: BVT.2733, an11β-HSD1selective inhibitor was connected with a peptideCKGGRAKDC that homes to white fat vasculature. CKGGRAKDC-BVT.2733(T-BVT) or an equimolar mixture of CKGGRAKDC and BVT.2733(NT-BVT) wasgiven to diet-induced obesity mice for two weeks through subcutaneous injection.Results: T-BVT decreased body weight gain, improved glucose tolerance anddecreased adipocyte size compared with vehicle treated mice. In adipose tissueT-BVT administration significantly increased adiponectin, vaspin mRNA levels; Inliver T-BVT administration decreased the mRNA level of phosphoenolpyruvatecarboxykinase (PEPCK), increased the mRNA levels of mitochondrial carnitinepalmi-toyltransferase-I (mCPT-I) and peroxisome proliferator-activated receptor α(PPARα). No significant differences in adipocyte size and hepatic gene expressionwere observed after treatment with NT-BVT compared with vehicle treated mice,though NT-BVT also decreased body weight gain, improved glucose tolerance, andincreased uncoupling protein-2(UCP-2) mRNA levels in muscle.Conclusion: These results suggest that an adipose tissue-targeted pharmacologicalinhibitor of11β-HSD1may prove to be a new approach for the treatment of obesityand metabolic syndrome.Part II: BVT.2733, a selective11β-hydroxysteroiddehydrogenase type1inhibitor, attenuates obesity andinflammation in diet-induced obese mice Objective: Inhibition of11β-hydroxysteroid dehydrogenase type1(11β-HSD1) isbeing pursued as a new therapeutic approach for the treatment of obesity andmetabolic syndrome; therefore, there is an urgent requirement to determine theeffect of11β-HSD1inhibitor, which has a suppressing function on glucocorticoidaction, on the inflammation of adipose tissue. The purpose of the present study is toexamine the effect of BVT.2733, a selective11β-HSD1inhibitor, oninflammation-related gene expression and macrophage infiltration in adipose tissuein C57BL/6J mice.Methods: C57BL/6J mice were fed at a normal fat diet (NC) or high fat diet (HFD).HFD treated mice were then administrated with BVT.2733(HFD+BVT) or vehicle(HFD) for four weeks. In vitro, the knock-down and overexpression of11β-HSD1were performed by lentiviral. Gene expression was analysed using real-timeRT-PCR.Results: BVT.2733not only decrease body weight gain and improve glucosetolerance but also decreased the expression of inflammation-related genes such asmonocyte chemoattractant protein1(MCP-1), tumor necrosis factor a (TNF-α) andthe number of macrophages in adipose tissue. In vitro, Pharmacological inhibition of11β-HSD1and RNA interference against11β-HSD1reduced the mRNA levels ofMCP-1and interleukin-6(IL-6). The expression of MCP-1and IL-6augmented by11β-HSD1overexpression was aslo attenuated by BVT.2733in J774A.1macrophages and3T3-L1preadipocyte.Conclusions: These results suggest that BVT.2733treatment could not onlydecrease body weight gain and improve glucose tolerance, but also suppress theinflammation of adipose tissue in diet-induced obese mice.11β-HSD1may be a verypromising therapeutic target for obesity and cardiovascular disease.