基于AMPK/SIRT1-FOXO1信号通路探讨哺乳期营养过剩对小鼠肥胖的影响  

Exploring the effects of overnutrition during lactation on mice obesity based on the AMPK/SIRT1-FOXO1 signaling pathway

作　　者：钱学艳[1] 郑毅 齐磊[1] 刘丹丹 梁虹 冯博 李继媛[1] 董艳梅[1] QIAN Xue-yan;ZHENG Yi;QI Lei;LIU Dan-dan;LIANG Hong;FENG Bo;LI Ji-yuan;DONG Yan-mei(School of Public Health,Qiqihar Medical College,Qiqihar,Heilongjiang 161006,China)

机构地区：[1]齐齐哈尔医学院公共卫生学院,黑龙江齐齐哈尔161006

出　　处：《现代预防医学》2024年第15期2839-2843,共5页Modern Preventive Medicine

基　　金：黑龙江省自然科学基金资助项目(LH2021H123);齐齐哈尔市科技计划联合引导项目(LHYD-2021009);齐齐哈尔医学科学院国自然重点培育项目(2021-ZDPY-005)。

摘　　要：目的明确哺乳期营养过剩影响小鼠肥胖过程中,腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)/去乙酰化酶1(sirtuin 1,SIRT1)-叉头框蛋白O1(forkhead box protein O1,FOXO1)信号通路蛋白翻译后修饰水平防治肥胖的新靶标及新策略。方法C57BL/6刚出生雄性小鼠随机分为对照组(control,CON,8只/乳母)和小窝组(small litter control group,SC,5只/乳母),3周断乳后给与标准膳食喂养6周至成年,CON组和SC组小鼠分别被分为两组:CON和高脂对照组(high fat control,HFC),SC和小窝HFC(small litter HFC,SHFC)组。CON和SC组小鼠继续食用标准膳食,HFC和SHFC组小鼠高脂膳食诱导肥胖7周。分期处死小鼠取材,酶法测量血脂,Western blot法检测蛋白的表达,苏木精-伊红染色法进行病理学观察。结果与CON或HFC相比,各阶段SC或SHFC组的体脂、体重、血清甘油三酯水平均升高(P<0.05),高密度脂蛋白胆固醇水平降低(P<0.05);16周末SHFC组小鼠肝细胞脂肪变性明显高于SC组。与CON或HFC、SC组比较,SC或SHFC组SIRT1、磷酸化AMPK蛋白持续降低(P<0.05),乙酰化FOXO1蛋白持续升高(P<0.05)。结论哺乳期营养过剩可通过AMPK/SIRT1-FOXO1信号通路的表观遗传学机制,持续降低AMPK蛋白的磷酸化,升高FOXO1蛋白的乙酰化,导致脂代谢紊乱,体脂积蓄和肥胖。Objective To elucidate the protein post-translational modification levels of the adenosine monophosphate-activated protein kinase(AMPK)/sirtuin 1(SIRT1)-forkhead box protein O1(FOXO1)signaling pathway in the process of lactation nutrient overload affecting obesity in mice,and to identify new targets and strategies for preventing obesity.Methods Newly born male C57BL/6 mice were randomly assigned to the control group(CON,8 pups/dam)and the small litter control group(SC,5 pups/dam).After weaning for 3 weeks,they were fed with a standard diet for 6 weeks to adulthood.The CON and SC groups were further divided into two subgroups:CON and high-fat control group(HFC);SC and small litter HFC(SHFC)group.Mice in the CON and SC groups continued to consume a standard diet,while mice in the HFC and SHFC groups were induced to obesity with a high-fat diet for 7 weeks.Mice were sacrificed at different time points for sample collection.Enzyme assays were utilized to measure lipid levels.Expression levels of proteins were analyzed by Western blotting,and liver cell steatosis were examined using Hematoxylin-Eosin(HE)staining.Results Compared with CON or HFC,the body fat,body weight,and serum triglyceride levels of the SC or SHFC groups were significantly higher(P<0.05),and the high-density lipoprotein cholesterol levels were lower(P<0.05)at each stage.At 16 weeks,the hepatic cell steatosis in the SHFC group was significantly higher than that in the SC group.Compared with CON or HFC,the levels of SIRT1 and phosphorylated AMPK protein in the SC or SHFC groups were continuously decreased(P<0.05),and the acetylated FOXO1 protein was continuously increased(P<0.05).Conclusion Nutrient overload during lactation can continuously reduce the phosphorylation of AMPK protein and increase the acetylation of FOXO1 protein through the epigenetic mechanism of the AMPK/SIRT1-FOXO1 signaling pathway,leading to lipid metabolism disorders,fat accumulation,and obesity.

关 键 词：肥胖 AMPK SIRT1 营养过剩 FOXO1 

分 类 号：R589.2[医药卫生—内分泌] R15[医药卫生—内科学]