贯叶金丝桃素和氨来呫诺联合用药抗肥胖及改善代谢的研究  

Anti-obesity effect of combined treatment of hyperforin and amlexanox on ob/ob mice

作　　者：陆思嘉 刘楚楚 徐俊亭 刘军力 陈素贞 Lu Sijia;Liu Chuchu;Xu Junting;Liu Junli;Chen Suzhen(Shanghai Diabetes Institute,Department of Endocrinology and Metabolism,Shanghai Key Laboratory of Diabetes Mellitus,Shanghai Jiaotong University Affiliated Sixth People′s Hospital,Shanghai 200233,China)

机构地区：[1]上海交通大学附属第六人民医院,上海市糖尿病研究所,上海市糖尿病重点实验室,200233

出　　处：《中华内分泌代谢杂志》2022年第9期798-805,共8页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金面上项目(82170863);上海市科学技术委员会启明星计划(21QA1407000)。

摘　　要：目的探讨中药单体贯叶金丝桃素(HPF)与氨来呫诺(AM)联合给药时,对抗肥胖及改善代谢紊乱的叠加治疗作用。方法采用ob/ob小鼠为肥胖小鼠模型,在HPF单药(2.5 mg/kg,腹腔注射)或与AM(50 mg/kg,灌胃)联合给药4周后,监测小鼠体重、摄食,检测血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平,并通过小动物核磁共振、代谢笼、糖耐量和胰岛素耐量检测及HE染色等方法,观察小鼠的体重变化、能量消耗、脂肪含量、糖代谢等的变化。Western印迹和酶联免疫吸附测定(ELISA)用以检测环磷酸腺苷(cAMP)-蛋白激酶A(PKA)信号通路。结果给药4周后,与对照组相比(平均体重54.07 g),HPF给药组的小鼠平均体重下降至51.33 g(P=0.042);与AM联合给药后,小鼠平均体重进一步降低至47.61 g(P=0.041),表现出明显的叠加效应。小鼠核磁共振结果显示,HPF给药后小鼠脂肪含量减少(P=0.011),表现为腹股沟白色脂肪和附睾旁白色脂肪的细胞直径都变小(P=0.014,P=0.032),产生棕色化趋势,棕色脂肪组织中白色脂肪浸润减少。然而,与HPF给药组相比,两药联合治疗并没有使白色脂肪细胞进一步变小或减少其在棕色脂肪组织的脂质积累。代谢笼实验显示,HPF处理的小鼠在光照期的氧气消耗率(P<0.001)和二氧化碳释放率(P=0.002)都显著高于对照组小鼠,HPF与AM的组合可以进一步提高小鼠的能量消耗。此外,HPF与AM联合给药可以进一步激活白色脂肪组织中的儿茶酚胺下游cAMP-PKA信号通路。当联合用药时,肥胖小鼠的胰岛素抵抗改善,肝脏三酰甘油含量减少(P=0.049),肝脏损伤指标血清ALT水平下降(P=0.008)。结论HPF和AM联合用药有望成为治疗肥胖、改善代谢紊乱、缓解儿茶酚胺抵抗的有效策略。Objective To investigate the effect of combined treatment of hyperforin(HPF)and amlexanox(AM)on obesity and metabolic disorders.Methods ob/ob mice were used as an obese mice model and treated with HPF alone(2.5 mg/kg intraperitoneal injection)or combined with AM(50 mg/kg,gavage administration)for 4 weeks.Their body weight and food intake were monitored,glucose tolerance test and insulin tolerance test were performed,serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected.Nuclear magnetic resonance was used to detect the body composition and metabolic cage was used to detect the energy consumption.After sampling,HE staining was used to observed the pathological change of fat and liver tissues,Western blotting and enzyme-linked immunosorbent assay(ELISA)were used to detect the cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway.Results Compared to the vehicle-treated mice(54.07 g),HPF-treated mice showed attenuated body weight gain(51.33 g,P=0.042)and reduced total fat mass(P=0.011);while administration of HPF in combination with AM(HPF/AM)further reduced the body weight(47.61 g,P=0.041).HE staining analysis showed that HPF alone or HPF/AM treatment both decreased the diameters of adipocytes and infiltration of white fat(P=0.014,P=0.032)in brown adipose tissues,which resulted in a trend of browning.However,HPF/AM-treatment didn′t further diminish adipocytes or reduce lipid accumulation in brown adipose tissues compared to HPF-treated mice.In addition,the basal oxygen consumption rate(VO2,P<0.001)and(VCO_(2),P=0.002)of HPF-treated mice were mainly elevated in the light phase relative to that of control mice;while HPF/AM-treatment further promote the energy consumption both in the dark phase and light phase.Notably,cAMP-PKA signaling pathway was obviously activated under HPF/AM-treatment in inguinal white adipose tissue.Moreover,HPF/AM-treatment showed beneficial effects on glucose metabolism and fatty liver,as indicated by improved insulin resistance,reduc

关 键 词：肥胖 贯叶金丝桃素 氨来呫诺 

分 类 号：R589.2[医药卫生—内分泌]