雄激素及其受体在有氧运动改善肥胖及肥胖相关疾病症状和血糖血脂中的作用

Roles of Androgen and Androgen Receptor in Aerobic Exercise Improving Blood Glucose and Lipid,Obesity and Related Symptoms of Rats

目的:研究肥胖及其相关疾病大鼠的血糖血脂异常是否与雄激素及雄激素受体水平的低下有关,并进一步探讨雄激素及其受体在运动改善血糖血脂中的作用及机制。方法:将8周高脂饮食、高脂饮食联合腹腔注射链脲佐菌素或维生素D3分别建立的肥胖(obesity,OB)、糖尿病(diabetes mellitus,DM)和动脉粥样硬化(atherosclerosis,AS)模型雄性大鼠随机分为OB组(n=8)、OB+运动组(EOB组,n=8)、DM组(n=10)、DM+运动组(EDM组,n=10)、AS组(n=8)、AS+运动组(EAS组,n=8)。运动方案为4周递增负荷中等强度有氧运动,每周6天,每天1次。另26只普通饮食大鼠随机分为3组:对照组(CON组,n=10),AR拮抗剂氟他胺包埋组(Flutamide组,n=8)和假手术组(Sham组,n=8)。采用双试剂直接法、ELISA和Western blot等方法分别检测大鼠血糖血脂和血清睾酮水平,以及肝脏、腓肠肌、脂肪的雄激素受体(AR)和磷酸烯醇式丙酮酸激酶(PEPCK)的蛋白水平。结果:1)与CON组大鼠比较,OB、DM和AS组大鼠出现血糖血脂紊乱,且伴随血清睾酮水平和肝脏、腓肠肌、脂肪组织中AR蛋白表达水平显著下调;2)疾病大鼠的甘油三酯(TG)和低密度脂蛋白(LDL)水平与睾酮水平显著负相关,空腹血糖(FBG)与睾酮水平未见相关;3)AR抑制剂氟他胺显著升高大鼠总胆固醇(TC)、TG和LDL水平;4)与对应的疾病组比较,EOB、EDM和EAS组大鼠睾酮和外周代谢器官的AR蛋白水平上调,PEPCK蛋白水平显著下调,且伴随着疾病症状和血糖血脂的改善。结论:1)肥胖、糖尿病和动脉粥样硬化雄性大鼠血糖血脂异常与雄激素/AR水平低下有关。2) 4周有氧运动对肥胖、糖尿病和动脉粥样硬化雄性大鼠疾病症状和血糖血脂紊乱的改善,可能与运动增加血清雄激素和外周代谢器官的AR蛋白水平,进而下调PEPCK等糖、脂代谢关键酶的表达水平有关。

Objective To determine whether the abnormal blood glucose and lipid of obese rats is related to the decrease of androgen and androgen receptor(AR),and explore effect of androgen/AR pathway on the exercise-induced improvement of blood glucose and lipid and its underlying mechanism.Methods Obesity(OB),diabetes mellitus(DM) or atherosclerosis(AS) was induced in rats feeding eightweek high fat diet,or plus intraperitoneal injection of small dose streptozotocin or plus vitamin D3 injection respectively. After the successful modelling,they were randomly divided into an OB(n=8),an OB plus exercise(EOB,n=8),a DM(n=10),a DM plus exercise(EDM,n=10),an AS(n=8) and an AS plus exercise(EAS, n=8) group. The exercise protocol consisted of four-week moderate intensity aerobic exercise,six times per week. In addition,26 rats fed with normal diet were divided to a control group(CON,n=10),an AR antagonist Flutamide embedded group(Flutamide,n=8) and a sham group(Sham,n=8). The blood glucose and lipid,fasting blood glucose(FBG) and fasting serum insulin(FINS) were detected. The serum testosterone concentration and protein levels of the AR and phosphoenolpyruvate carboxy kinase(PEPCK) in the liver, gastrocnemius and adipose tissue were determined using the enzyme-linked immunosorbent assay and Western blotting respectively.Results Compared with the rats in CON group,a significant decrease was observed in the average serum testosterone,AR protein level in the liver,gastrocnemius and adipose tissue of the OB,DM and AS rats with abnormal blood glucose and lipid. The average triglyceride(TG) and low density lipoprotein(LDL) of the unhealthy rats had a significant and negative correlation to the average serum testosterone level,while there was no correlation between the FBG and the latter. Flutamide,the AR antagonist,increased the total cholesterol(TC),TG and LDL levels in the serum significantly. Compared with their respective disease groups,EOB,EDM and EAS groups showed a significant increase in the serum testosterone concentration and AR protein level of peripheral metabolic organs, but a significant decrease in the protein level of PEPCK as well as the improved blood glucose and lipid and relieved symptoms.Conclusions The abnormal blood glucose and lipid of OB,DM and AS male rats were associated with the decreased androgen/AR level. 2) The improvement of blood glucose and lipid and the alleviation of symptoms induced by four-week aerobic exercise of OB,DM and AS rats were likely associated with the increase of the serum androgen concentration and AR protein level in peripheral metabolic organs,as well as the subsequently decreased expression of key regulatory gluconeogenic enzyme PEPCK.