| Objective:The Metabolic syndrome (MS) consists of a constellation factors namely diabetes, hypertension, abdominal obesity, lipid disorders and insulin resistance (IR). Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been postulated as a novel treatment for obesity and the metabolic syndrome. BVT.2733 as a new, small molecule inhibitor of mouse 11β-HSD1 is highlighted recently. In addition, potent activation of peroxisome proliferator activated receptor gamma (PPARγ) by Thiazolidinediones (TZDs) can alleviate IR by influence glycometabolism and gene expression. However, it is now clear that obesity is associated with a state of chronic low-level inflammation, which related to IR, Type 2 Diabetes Mellitus (T2DM) and Cardiovascular Disease (CVD), and inhibition of inflammatory state becomes a therapeutic strategy. Our experiments focused on compare the effects of BVT.2733 and Pioglitazone (PGZ) on glycometabolism and inflammation state in diet-induced obesity (DIO) mice.Methods:1. Animals: Male C57BL/6J mice were purchased from Shanghai, and grouped into normal mice (Normal) and diet-induced obesity mice (DIO), fed with normal diet or high-fat diet for 20 weeks. Then, DIO mice were divided into BVT.2733 mice (BVT.2733), PGZ mice (PGZ) and BVT.2733+PGZ mice (BVT.2733+PGZ). Mice were administrated with vehicle, BVT.2733, PGZ or BVT.2733+PGZ for 2 weeks. After that, mice were killed, serum was prepared from trunk blood samples and epididymal fat were isolated from mice.2. Indexes related with glycometabolism were measured: Body weight was measured before and after administration, body gain was calculated every group. The size of adipocytes of epididymal fat was performed by Immunohistochemistry. Fasting blood glucose and serum insulin were measured. All these indexes related with glycometabolism were compared between groups.3. Indexes related with inflammation were measured: Serum TNF-αwas detected by ELISA. Total RNA was prepared from frozen epididymal fat and treated with DNase. The cDNA was prepared from all of the total RNA samples using the TaqMan reverse transcription reagent. Real-time PCR was used to quantify mRNA levels of TLR4 isolated from epididymal fat. Also, these indexes related with inflammation were compared between groups.Results:1. Compared with Normal mice, adipocytes were significantly enlarged in Obesity mice, and body weight increased. Similarly, blood glucose were all increased (P < 0.01). After administration with drugs, adipocytes were diminished (P < 0.01). Moreover, BVT.2733 could reduce weight gain significantly (P < 0.01) and decrease serum insulin (P < 0.05). Different to BVT.2733, weight change was not obvious but blood glucose and serum insulin were all decreased notablely (P < 0.05) when treated with PGZ. However, when BVT.2733 and PGZ were used together, there was no change in blood glucose and serum insulin increased (P < 0.05).2. Compared with Normal mice, serum TNF-αand the expression of TLR4 mRNA in adipose tissue were significantly increased in Obesity mice (P < 0.05). After treated with drugs, the expression of TLR4 mRNA was decreased (P < 0.05). However, the serum TNF-αlevel didn't change significantly. Unexpected, serum TNF-αincreased notablely in BVT+ PGZ mice.Conclusion:Both BVT.2733 and PGZ used alone can improve glycometabolism disturbance, decrease the expression of TLR4 mRNA in adipose tissue but have little effect on systematic inflammation in DIO mice. BVT.2733 is expert in control body weight while PGZ is good at improve hyperglycemia. But these effect were reversed when used in combination. |
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