达格列净调节肥胖2型糖尿病小鼠皮下白色脂肪棕色化作用研究  

Effects of dapagliflozin on browning of subcutaneous white adipose tissue in obese type 2 diabetic mice

作　　者：董靖 刘敏 向光大 乐岭 向林 Dong Jing;Liu Min;Xiang Guangda;Yue Ling;Xiang Lin(General Hospital of Central Theater Command,Wuhan 430070,China)

机构地区：[1]中部战区总医院内分泌科,武汉430070

出　　处：《国际内分泌代谢杂志》2025年第1期16-22,共7页International Journal of Endocrinology and Metabolism

基　　金：中部战区总医院育英计划(ZZYCZ202115)。

摘　　要：目的探究达格列净调节肥胖2型糖尿病(T2DM)小鼠皮下白色脂肪组织(WAT)棕色化作用。方法选取雄性C57BL/6J小鼠30只,10只作为正常对照组,其余20只高脂饲养注射链脲佐菌素(STZ)构建肥胖T2DM小鼠模型。共有17只小鼠建模成功,将其分为肥胖T2DM组8只、肥胖T2DM+达格列净干预组9只。各组小鼠分别给予1 mg·kg^(-1)·d^(-1)达格列净或生理盐水灌胃,连续干预8周。记录小鼠干预期间体重变化;取材后,记录小鼠WAT及肝脏组织质量;检测小鼠静脉空腹血糖(FBG)及血清游离脂肪酸(FFA)、甘油三酯(TG)水平;苏木精伊红(HE)染色观察WAT形态学;反转录聚合酶链反应(RT-PCR)和蛋白质印迹(Western-blot)检测小鼠WAT棕色化、炎性基因以及血管内皮生长因子-A(VEGF-A)的表达;免疫荧光染色观察WAT血管分布情况。结果与肥胖T2DM组比较,达格列净干预减轻小鼠体重、肝脏质量,降低静脉FBG及血清FFA、TG水平,上调棕色化基因解耦联蛋白-1(UCP-1)、过氧化物酶体增殖物激活受体γ共激活因子-1α(PGC-1α)、诱导细胞凋亡DFF45样效应因子A(CIDEA)表达(P均<0.05),降低炎性基因白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)表达(P均<0.05),增加WAT血管分布并促进VEGF-A表达(P<0.05),促进WAT组织自噬作用。结论达格列净可能通过自噬作用调节WAT炎性水平及血管生成改善肥胖T2DM糖脂代谢紊乱,促进WAT棕色化。ObjectiveTo investigate the effect of dapagliflozin on subcutaneous white adipose tissue(WAT)browning in obese type 2 diabetic(T2DM)mice.MethodsA total of 30 male C57BL/6J mice were selected,with 10 mice used as normal control group,and the other 20 mice fed with high-fat and injected with streptozotocin(STZ)to construct an obese T2DM mouse model.There were 17 mice successfully modeled,and 8 mice were allocated to obese T2DM group,9 mice allocated to obese T2DM+dapagliflozin intervention group.The mice in each group were orally administered with either 1 mg·kg^(-1)·d^(-1) dapagliflozin or vehicle(physiological saline)for 8 weeks.Body weight changes during the treatment period were recorded.After sacrifice,liver and WAT mass of each group were measured.Fasting blood glucose(FBG),serum levels of free fatty acids(FFA),and triglycerides(TG)were determined.Hematoxylin-eosin(HE)staining was performed to observe the morphology of WAT.Reverse transcription-polymerase chain reaction(RT-PCR)and Western-blot were used to detect the expression of browning-related genes,inflammatory genes,and vascular endothelial growth factor A(VEGF-A)in mouse WAT.Immunofluorescence staining was conducted to evaluate the vascular distribution in WAT.ResultsCompared with the obese T2DM group,dapagliflozin decreased body and liver weight,and reduced the levels of FBG,FFA,and TG.Dapagliflozin treatment also upregulated the expression of browning-related genes such as UCP-1,PGC-1α,and CIDEA(all P<0.005),while downregulating the expression of inflammatory genes such as IL-6,TNFα,and MCP-1(all P<0.005).Dapagliflozin increased vascular distribution and enhanced VEGF-A expression in WAT(all P<0.005).Additionally,dapagliflozin promotes autophagy in adipose tissue.ConclusionDapagliflozin induces WAT browning via autophagy to modulate inflammation level and promote vascularization in obese T2DM mice.

关 键 词：达格列净 肥胖 糖尿病 白色脂肪棕色化 

分 类 号：R58[医药卫生—内分泌]