长期高脂饮食对小鼠抑郁样行为的影响及BDNF的代谢失衡机制

Effects of long-term high fat diet on depressive-like behavior in mice and mechanism of metabolic imbalance of BDNF

目的:研究长期高脂饮食对小鼠糖代谢、抑郁样行为影响和大脑内的proBDNF、mature BDNF和p75NTR表达变化。方法:选取16只8周龄C57BL/6小鼠,随机分为高脂饮食组和标准饮食组,每组8只,分别给予标准饮食(standard diet,STD)和高脂饮食(high fat diet,HFD),每周测量体质量、食物摄入量,每4周测量空腹血糖。30周后,采用葡萄糖耐量实验和胰岛素耐量实验测定胰岛功能,采用强迫游泳实验(forced swim test,FST)和悬尾实验(tail suspension test,TSD)检测小鼠的抑郁行为。收集小鼠大脑组织,Elisa法测定proBDNF、mature BDNF和p75NTR浓度,分析以上检测因子与小鼠体质量、血糖和抑郁行为的相关性。结果:HFD组小鼠出现肥胖、高血糖和胰岛素抵抗,伴有明显抑郁。HFD组小鼠脑内proBDNF浓度[(4.95±1.12)pg/μg]较STD组[(2.19±0.19)pg/μg]明显增加(t=2.68,P<0.05),mature BDNF浓度[(1.39±0.18)pg/μg]较STD组[(2.26±0.23)pg/μg]明显下降(t=-2.90,P<0.05),p75NTR浓度[(3.56±1.23)pg/μg]较STD组[(1.42±0.16)pg/μg]明显增加(t=5.78,P<0.05)。Spearman相关分析显示proBDNF与p75NTR与体质量、血糖和不动时间呈正相关;mature BDNF与体质量、血糖和不动时间呈负相关。结论:长期HFD引起proBDNF和mature BDNF失平衡,proBDNF-p75NTR通路上调可能是代谢异常和抑郁相互作用的共同机制,调节proBDNF和mature BDNF信号平衡,可能对代谢障碍伴发的抑郁起到积极的作用。

Objective:To study the effects of long-term high fat diet on glucose metabolism,depressive-like behavior and the expression of proBDNF/mature BDNF and p75NTR in brain of mice.Methods:Totally 168-week-old C57BL/6 mice were randomly divided into two groups with 8 in each group.The mice in STD group were given standard diet(STD)and the mice in HFD group were given high fat diet(HFD).The body weight and food intake were measured every week,and the fasting blood glucose was measured every 4 weeks.After 30 weeks,glucose tolerance test and insulin tolerance test were used to measure islet function,while forced swimming test and tail suspension test were used to detect depression behavior.The brain tissues of mice were collected and the concentrations of proBDNF,mature BDNF and p75NTR were measured by Elisa.The correlation between the above factors and body weight,blood glucose and depression behavior of mice was analyzed.Results:Obesity,hyperglycemia,insulin resistance and depression were observed in HFD group.The concentration of proBDNF in HFD group((4.95±1.12)pg/μg)was significantly higher than that in STD group((2.19±0.19)pg/μg)(t=2.68,P<0.05),the concentration of mature BDNF((1.39±0.18)pg/μg)was significantly lower than that in STD group((2.26±0.23)pg/μg)(t=-2.90,P<0.05),and the concentration of p75NTR((3.56±1.23)pg/μg)was significantly higher than that in STD group((1.42±0.16)pg/μg)(t=5.78,P<0.05).Spearman correlation analysis showed that proBDNF and p75NTR were positively correlated with body weight,blood glucose and immobile time,while mature BDNF was negatively correlated with body weight,blood glucose and immobile time.Conclusion:Imbalance of proBDNF and mature BDNF,the upregulation of proBDNF-p75NTR pathway caused by long-term HFD may be the mechanism of the interaction between metabolic abnormality and depression.Regulating the balance of proBDNF and material BDNF signal pathway may play a positive role in the emotional disorders associated with metabolic disorders.