噻唑烷二酮通过脂联素介导的AMPK信号通路抑制鸡的生长

Thiazolidinedione Inhibits Chicken Growth via Adiponectin-mediated AMPK Signaling Pathway

噻唑烷二酮(thiazolidinedione,TZD)是一种治疗胰岛素抵抗的口服糖尿病药物,滥用或不当使用TZD对动物和人类的健康具有不良影响。本研究探讨了TZD对健康雏鸡生长和代谢的影响以及这一过程的潜在机制。80只6日龄雏鸡分为对照组(雌雄各20只)、试验组(雌雄各20只),对照组的鸡不灌服TZD,试验组的鸡连续14 d每日灌服25 mg·(kg·d)^(-1)TZD,检测雏鸡的生长情况;利用生化试剂盒检测腺嘌呤核苷三磷酸(ATP)和脂联素水平、生长代谢相关激素浓度、线粒体功能;通过RT-PCR和蛋白质印迹法检测调节细胞代谢和增殖相关基因的mRNA和蛋白质水平。结果发现,TZD显著降低了雏鸡的平均日增重以及血清ATP、胰岛素(insulin,INS)、生长激素(growth hormone,GH)和胰岛素样生长因子1(insulin-like growth factor 1,IGF1)的水平(P<0.05),而提高了脂联素和胰岛素样生长因子结合蛋白2(IGFBP2)的水平(P<0.05)。TZD还降低了雏鸡肝、肾和肌肉的ATP水平及线粒体酶活性(P<0.05)。此外,TZD的摄入使雏鸡脂联素及其受体、AMP活化蛋白激酶α2(AMPKα2)、p21和p27的mRNA及蛋白表达增强(P<0.05),而INS及其受体、IGF1及其受体、磷脂酰肌醇-3-激酶(PI3K)、AKT、哺乳动物雷帕霉素靶蛋白(mTOR)、细胞周期蛋白依赖性激酶2(CDK2)和细胞周期蛋白E1(cyclin E1)的mRNA和蛋白表达受到抑制(P<0.05)。TZD通过脂联素介导的AMPK信号通路降低了雏鸡生长代谢相关激素水平和线粒体功能,该信号通路抑制其下游PI3K/AKT/mTOR,进一步导致p21/p27表达增加以及CDK2/Cyclin E1表达降低,从而抑制雏鸡生长和代谢组织中的细胞增殖。综上表明,TZD通过调节脂联素介导的AMPK信号通路对鸡的生长产生不利影响,这为临床实践与畜禽生产中避免滥用或不当使用TZD提供了一定的理论依据。

Thiazolidinedione(TZD)is an oral anti-diabetic drug for the treatment of insulin resistance.Abuse or improper use of TZD has adverse effects on animal and human health.This study explores effects of TZD on the growth and metabolism of chicks and underlying mechanisms of this process.Eighty chicks at the age of 6-day-old were divided into a control group(20 females,20 males)and an experimental group(20 females,20 males).Chicks in the control group were administered without TZD,chicks in the experimental group were daily administrated with 25 mg·(kg·d)^(-1)TZD by gavage for 14 days,and the growth of chicks was measured.The biochemical kits were used to detect the levels of adenosine triphosphate(ATP)and adiponectin,the concentrations of growth and metabolism-related hormones,and the function of mitochondria.The mRNA and protein expressions of genes which are associated with cell metabolism and proliferation were detected by RT-PCR and western blotting.Results showed that TZD treatment significantly decreased the average daily gain of chicks(P<0.05).Serum ATP,insulin(INS),growth hormone(GH),and insulin-like growth factor 1(IGF1)levels were reduced in TZD-treated group(P<0.05),while adiponectin and insulin-like growth factor binding protein 2 levels was improved(P<0.05).TZD also decreased ATP levels and mitochondrial enzyme activities in the liver,kidney and muscle of chicks.Moreover,mRNA and protein expressions of adiponectin and its receptors,AMP-activated protein kinaseα2(AMPKα2),p21 and p27 were enhanced in TZD-treated chicks(P<0.05),whereas mRNA and protein expressions of INS and its receptor,IGF1 and its receptor,phosphatidylinositol-3-kinase(PI3K),AKT,mammalian target of rapamycin(mTOR),Cyclin-dependent kinase 2(CDK2)and Cyclin E1 were inhibited(P<0.05).The growth metabolism-related hormones and mitochondrial function in TZD-treated chicks were down-regulated by the adiponectin-mediated AMPK signaling pathway,which inhibited its downstream PI3K/AKT/mTOR,and further led to increased expressions of p21/p27 and decreased expressions of CDK2/Cyclin E1,this inhibiting the cell proliferation in growth and metabolic tissues of chicks.Our findings suggest that TZD has an adverse effect on chicken growth through regulating the adiponectin-mediated AMPK signaling pathway,this provides a certain theoretical basis for avoiding the abuse or improper use of TZD in clinical practice and animal production.