Study on the Safety and Efficacy of Disulfiram in the Treatment of Obesity in Mice
Objective:To observe the safety and efficacy of disulfiram in the treatment of obesity in mice.Methods:Ten 6-week-old C57BL/6J male mice were randomly divided into disulfiram group(disulfiram dissolved in corn oil,300 mg/(kg·d)and control group(equivalent amount of corn oil),with 5 mice in each group.The mice were administered once a day by intragastric administration for 2 weeks,during which high-fat diet was still given.Food consumption and body weight of the mice were monitored during the disulfiram administration.Serum,white adipose pad of epididymis,brown adipose tissue in the scapular area,and liver were taken after administration.White and brown adipose tissue,and liver were stained with HE,and the cell morphology was observed.Lipid droplets and mitochondria in brown adipocytes were observed under electron microscopy.Realtime-qPCR was used to detect the relative mRNA expression levels of Ucp1,Fabp4,Prdml6,and Cidea in brown adipose tissue,while Western blot was used to detect the protein expression level of Ucp1.Levels of aminotransferase ALT and AST in serum was also detected.Ten C57BL/6J male mice aged 8 weeks were randomly divided into disulfiram group(disulfiram 300 mg/(kg·d)and control group(equivalent amount of com oil).They were intragastrically administered once a day for two weeks.After administration,HE staining of the brown adipose tissue and liver were performed,and ALT and AST contents in serum were detected.Ten C57BL/6J male mice aged 8 weeks were randomly divided into disulfiram group(disulfiram 300 mg/(kg-d)and control group(equivalent amount of com oil).They were intragastically administered once a day for four weeks,and HE staining of the liver was performed.Serum levels of ALT and AST were measured.C57BL/6J embryonic mice with a gestational age of 13.5 days were selected for primary fibroblast culture.They were divided into disulfiram group(5 mg/L disulfiram)and control group(equivalent amount of DMSO)and induced to differentiate into brown adipocytes.After 8 days of differentiation,oil red O staining was performed to observe the formation of lipid droplets,and the relative mRNA and protein expression levels of Ucpl,Fabp4,Prdml6,and Cidea were detected.Results:During the administration,there was no significant difference in food intake and weight changes between the disulfiram group and the control group(P＞0.05).After administration,there was no significant difference in the size of white adipocytes between the two groups.The diameter of brown adipocytes and intracellular lipid droplets in the disulfiram group of mice were significantly increased(P＜0.05),but there was no significant difference in the number of lipid droplets,mitochondrial morphology and mitochondrial number(P＞0.05).The mRNA expression of Cidea and Prdm16 in brown adipose tissue of mice in the disulfiram group were decreased(P＜0.05).For mice with normal weight,after 2 weeks of administration of disulfiram,the lipid droplets of brown adipocytes were also enlarged.The results of cell experiments showed that the formation of lipid droplets was significantly reduced in the disulfiram group,and the mRNA expression of Ucpl,Cidea,and Prdm16 was significantly reduced(P＜0.05);The protein expression of Ucpl was significantly reduced(P＜0.05).Both obese and normal weight mice showed significant liver cell edema after 2 weeks of administration of disulfiram,with elevated levels of ALT and AST in serum(P＜0.05).Normal weight mice also showed significant liver cell edema after 4 weeks of disulfiram administration,with elevated levels of ALT and AST(P＜0.05).Conclusion:Short term use of disulfiram has no significant effect on weight loss of diet-induced obese mice;disulfiram can inhibit the differentiation of mice's brown adipocytes both in vivo and in vitro.Short-term use of disulfiram can cause liver damage.The safety and effectiveness of disulfiram in weight loss treatment are not ideal enough.
NETL
NSTL
万方数据
维普
