Establishment of A Mouse Model of Obesity and Depression Comorbidity and Its Application in Pharmacological Study of Tripterine

Hongyu CHI; Xuemin YAO; Guoxin ZHANG; Congmin TIAN; Tingjun LIANG; Jiahao LI; Jun YANG; Chunyan ZHU; Na LIN

doi:10.13422/j.cnki.syfjx.20221341

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Establishment of A Mouse Model of Obesity and Depression Comorbidity and Its Application in Pharmacological Study of Tripterine

更新时间：2022-09-01

- Establishment of A Mouse Model of Obesity and Depression Comorbidity and Its Application in Pharmacological Study of Tripterine
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 14, Pages: 81-91(2022)
- 作者机构：
  
  1.广州中医药大学中药学院，广州 510405
  2.中国中医科学院中药研究所，北京 100700
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20221341
  CLC： R2-0;R33;R285;R246.6
- Received：18 March 2022，
  
  Published Online：27 May 2022，
  
  Published：20 July 2022
- 稿件说明：
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池宏宇,姚雪敏,张国鑫等.肥胖与抑郁共病小鼠模型建立及在雷公藤红素药效药理研究中的应用[J].中国实验方剂学杂志,2022,28(14):81-91.

CHI Hongyu,YAO Xuemin,ZHANG Guoxin,et al.Establishment of A Mouse Model of Obesity and Depression Comorbidity and Its Application in Pharmacological Study of Tripterine[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(14):81-91.
池宏宇,姚雪敏,张国鑫等.肥胖与抑郁共病小鼠模型建立及在雷公藤红素药效药理研究中的应用[J].中国实验方剂学杂志,2022,28(14):81-91. DOI： 10.13422/j.cnki.syfjx.20221341.

CHI Hongyu,YAO Xuemin,ZHANG Guoxin,et al.Establishment of A Mouse Model of Obesity and Depression Comorbidity and Its Application in Pharmacological Study of Tripterine[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(14):81-91. DOI： 10.13422/j.cnki.syfjx.20221341.

摘要

目的

拟建立一种基于神经炎症的肥胖合并抑郁（COM）小鼠模型，并观察雷公藤红素对COM小鼠的药效作用及初步药理机制。

方法

C57BL/6J小鼠随机分为正常组（Chow）、肥胖组（DIO）、肥胖抑郁共病组（COM），COM组采用高脂饮食喂养和潮湿垫料慢性应激12周，建立小鼠肥胖抑郁共病模型。C57BL/6J小鼠随机分为Chow组、COM组、肿瘤坏死因子-

（TNF-

）敲低组，TNF-

敲低组通过脑立体定位在杏仁核注射TNF-

shRNA腺相关病毒，下调杏仁核中TNF-

表达量。C57BL/6J小鼠随机分为Chow组、DIO组、肥胖+雷公藤红素低剂量组（DIO-0.5 mg·kg

-1

）、肥胖+雷公藤红素高剂量组（DIO-1.0 mg·kg

-1

）、COM组、共病+雷公藤红素低剂量组（COM-0.5 mg·kg

-1

）、共病+红素高剂量组（COM-1.0 mg·kg

-1

）。记录体质量、进食量、葡萄糖耐量、白/棕脂率、血清总胆固醇（TC）、甘油三酯（TG）、高/低密度脂蛋白胆固醇（HDL-C、LDL-C）含量，评估各组小鼠肥胖程度；强迫游泳实验（FST）、悬尾实验（TST）和旷场实验，评估各组小鼠抑郁程度；免疫荧光检测小鼠各个脑神经核团神经肽Y、色氨酸羟化酶2（TPH2）、脑源性神经营养因子（BDNF）等蛋白表达含量；相关性分析检测各组小鼠肥胖和抑郁指标相关性。

结果

与Chow和DIO组比较，COM小鼠表现为肥胖和抑郁；肥胖表现为体质量和食物摄入明显增加（

0.05，

0.01），中央杏仁核中NPY表达明显增加；抑郁表现为FST和TST中的不动时间显著增加（

0.01）、中缝背核（DRN）和杏仁核基底外侧核（BLA）中TPH2阳性5-羟色胺能神经元数量明显减少。COM小鼠BLA中TNF-

蛋白的下调能减少FST和TST中的不动时间（

0.05，

0.01），明显增加BLA中TPH2/BDNF阳性神经元，肥胖表现没有显著变化。在DIO小鼠中，0.5 mg·kg

-1

雷公藤红素给药9 d显著降低葡糖糖耐量60 min血糖（

0.01）、摄食量（

0.05）；而COM小鼠中，1.0 mg·kg

-1

雷公藤红素需给药14 d以显著降低葡糖糖耐量30 min血糖（

0.01）、摄食量（

0.05）和悬尾不动时间（

0.01），以及能使BLA和DRN中TPH2-BDNF双标细胞数量增加，TMEM119染色的细胞体面积显著减少。

结论

在能量环境双重压迫条件下可以成功建立肥胖合并抑郁的小鼠模型；雷公藤红素能有效干预肥胖-抑郁共病，其机制可能与抑制中枢神经炎症有关。

Abstract

Objective

To establish a neuroinflammation-based obesity and depression comorbidity （COM） model in mice and explore the pharmacodynamics and preliminary pharmacological mechanism of tripterine on COM mice.

Method

C57BL/6J mice were randomly divided into a normal group （Chow）， a diet-induced obesity group （DIO）， and a COM group. The mice in the COM group were fed on a high-fat diet and chronically stressed with moist litter for 12 weeks to establish the COM model. C57BL/6J mice were randomly divided into a Chow group， a COM group， and a tumor necrosis factor-

（TNF-

） knock-down group. In the TNF-

knock-down group， TNF-

shRNA adeno-associated virus was injected into the amygdala through brain stereotaxis， and the expression of TNF-

in the amygdala was down-regulated. C57BL/6J mice were randomly divided into a Chow group， a DIO group， a DIO + low-dose tripterine group （0.5 mg·kg

-1

）， a DIO + high-dose tripterine group （1.0 mg·kg

-1

）， a COM group， a COM + low-dose tripterine group （0.5 mg·kg

-1

）， and a COM + high-dose tripterine group （1.0 mg·kg

-1

）. The body weight， food intake， glucose tolerance， white/brown fat ratio， serum total cholesterol （TC）， triglyceride （TG）， and high-/low-density lipoprotein cholesterol （HDL-C and LDL-C） content were recorded， and obesity of mice in each group was evaluated. Forced swimming test （FST）， tail suspension test （TST）， and open field test were used to evaluate the degree of depression of mice in each group. Immunofluorescence staining was used to detect the protein expression levels of neuropeptide Y， tryptophan hydroxylase 2 （TPH2）， and brain-derived neurotrophic factor （BDNF） in various brain nuclei of mice. Correlation analysis was used to detect the correlation of obesity and depression indexes.

Result

The comparison of the Chow group and the DIO group indicated that COM mice showed obesity and depression. To be specific， obesity was manifested as increased body weight and food intake （

0.05，

0.01）， as well as increased NPY expression in the central amygdala， and depression was manifested as prolonged immobility time in FST and TST （

0.01）， and reduced TPH2-positive 5-hydroxytryptamine neurons in the dorsal raphe nucleus （DRN） and basolateral nucleus of the amygdala （BLA）. The down-regulation of TNF-

protein in BLA of COM mice shortened the immobility time in FST and TST （

0.05，

0.01）， increased TPH2/BDNF-positive neurons in BLA， and showed no significant changes in obesity. In DIO mice， the administration of 0.5 mg·kg

-1

tripterine for 9 days significantly decreased the 60 min blood glucose in glucose tolerance （

0.01） and food intake （

0.05）. In COM mice， 1.0 mg·kg

-1

tripterine was administered for 14 days to significantly decrease 30 min blood glucose in glucose tolerance （

0.01）， and food intake （

0.05）， and immobility time in TST （

0.01）， increase TPH2-BDNF double-labeled cells in BLA and DRN， and reduce the area of TMEM119-stained cells.

Conclusion

The model of obesity and depression comorbidity can be properly induced in mice under the condition of dual stress of energy environment. Tripterine can effectively interfere with obesity-depression comorbidity， and its mechanism may be related to the inhibition of central nervous system inflammation.

关键词

Keywords

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