长期低剂量双酚A干扰雄性小鼠胰岛素敏感性和糖异生的作用研究

Study on effects of long-term low-doses bisphenol A exposure on insulin sensitivity and gluconeogenesis in male mice

目的研究长期低剂量双酚A(bisphenol A,BPA)暴露对不同营养条件下成年雄性小鼠(雄鼠)糖代谢稳态的作用与分子机制。方法将42只7~8周龄的雄鼠分为4组,两组为100μg/(kg·bw)BPA暴露组(BPA组,n=11),分别喂以普通饲料(normal diet,ND)和高脂饲料(high fat diet,HFD),另两组为对照组(纯橄榄油,CON组,n=10),同样分别喂以ND和HFD,每隔1日灌胃染毒,持续5个月;分别于染毒后第1和第3个月时检测糖代谢相关指标,在5个月时处死小鼠并检测胰岛素信号通路关键蛋白磷酸化水平、肝糖原含量以及糖代谢相关基因的表达情况。结果ND-BPA组小鼠染毒1个月时,胰岛素敏感性略有增强(P<0.05),糖异生能力增强(P<0.05),饱腹状态下血清胰岛素水平[(0.39±0.06)mg/dL]降低(P<0.05),暴露3个月后小鼠饱腹血糖[(190.47±16.71)mg/dL]升高(P<0.05),葡萄糖耐量受损(P<0.05),糖异生能力明显增强(P<0.05),暴露5个月时小鼠胰岛素信号通路被显著激活,肝糖原含量差异无统计学意义(P>0.05);而HFD饲养条件下,BPA暴露组小鼠饱腹和空腹状态下血糖和血清胰岛素水平及胰岛素敏感性差异均无统计学意义(均P>0.05),但葡萄糖耐量增强(P<0.05),糖异生水平降低(P<0.05),暴露5个月时小鼠的胰岛素信号通路无明显改变(P>0.05),肝糖原含量明显降低(P<0.05)。结论长期低剂量的BPA暴露可以轻度改善普通饮食小鼠的胰岛素敏感性,增强小鼠糖异生能力;而高脂饮食条件下,相同剂量的BPA暴露可以使小鼠葡萄糖耐量水平增加,糖异生水平受到抑制,可部分缓解高脂饮食引起的糖代谢紊乱。

Objective To investigate the effects and molecular mechanisms of long-term exposure to low-dose bisphenol A(BPA)on glucose metabolism homeostasis in adult male mice under different nutritional conditions.Methods A total of 42 male mice aged 7-8 weeks were randomly divided into four groups.Two groups(BPA groups,n=11)were treated with 100μg/(kg·bw)BPA in combination with normal diet(ND)or high fat diet(HFD)respectively,and the other two groups(control groups,n=10)were treated with olive oil in combination with ND or HFD respectively.The animals were administered by gavage every other day for 5months.The indexes related to glucose metabolism were detected at the first and third months after exposure.The mice were killed at 5 months,and the phosphorylation level of key proteins of insulin signaling pathway,liver glycogen content and the expression of glucose metabolism related genes were detected.Results Mice in ND-BPA group showed mildly improved insulin sensitivity(P<0.05)and gluconeogenesis capacity(P<0.05),and down-regulated serum insulin concentrations under satiety[(0.39±0.06)mg/dL]after the first month(P<0.05).The satiety blood glucose[(190.47±16.71)mg/dL]of mice after three-month exposure increased(P<0.05),with impaired glucose tolerance(P<0.05),and the ability of gluconeogenesis was significantly enhanced(P<0.05).After five-month exposure,insulin signaling pathway was significantly activated in mice,and there was no statistically significant difference in liver glycogen content(P>0.05).Under high fat feed feeding conditions,there were no statistically significant differences blood glucose,serum insulin concentrations and insulin sensitivity in the BPA-treated groups between satiety and fasting(all P>0.05),but the glucose tolerance increased(P<0.05)and gluconeogenesis decreased(P<0.05).After five-month exposure,there was no statistically significant change in insulin signaling of mice(P>0.05),but the liver glycogen content was significantly reduced(P<0.05).Conclusion The long-term exposure to low-dose BPA can slightly improve the insulin sensitivity and the gluconeogenesis capacity of ND mice,while under high fat diet,BPA exposure of the same dose can induce both increased glucose tolerance and inhibited gluconeogenesis capacity,which could partly alleviate the imbalanced glucose homeostasis caused by high fat diet.