上海交通大学学报(医学版) ›› 2023, Vol. 43 ›› Issue (9): 1131-1144.doi: 10.3969/j.issn.1674-8115.2023.09.007
• 论著 · 基础研究 • 上一篇
收稿日期:
2023-04-06
接受日期:
2023-09-03
出版日期:
2023-09-28
发布日期:
2023-09-28
通讯作者:
麻静,赵旭赟
E-mail:kaimin_wu2019@163.com;majing3436@163.com;xuyunzhao@shsmu.edu.cn
作者简介:
吴凯敏(1995—),女,硕士生;电子信箱:kaimin_wu2019@163.com。
基金资助:
WU Kaimin1(), MA Jing1(), ZHAO Xuyun2()
Received:
2023-04-06
Accepted:
2023-09-03
Online:
2023-09-28
Published:
2023-09-28
Contact:
MA Jing,ZHAO Xuyun
E-mail:kaimin_wu2019@163.com;majing3436@163.com;xuyunzhao@shsmu.edu.cn
Supported by:
摘要:
目的·研究间歇性禁食(intermittent fasting,IF)联合产热脂肪活化对小鼠肥胖的治疗和预防作用。方法·取8周龄雄性C57BL/6J正常小鼠以高脂饲料喂养4个月,构建肥胖小鼠模型作为肥胖治疗实验对象;另取8周龄雄性C57BL/6J正常小鼠作为肥胖预防实验对象。2种实验小鼠均分为对照组、隔日腹腔注射CL316243(β3-肾上腺素能受体激动剂,CL)组、IF组、IF联合隔日腹腔注射CL组。肥胖治疗实验小鼠与肥胖预防实验小鼠分别干预38 d和124 d,干预期间均以高脂饲料喂养。每2 d记录小鼠摄食量和体质量;实验结束后,检测小鼠外周血葡萄糖浓度,收集棕色脂肪组织(brown adipose tissue,BAT)、腹股沟白色脂肪组织(inguinal white adipose tissue,iWAT)、附睾白色脂肪组织(epididymal white adipose tissue,eWAT)和肝脏样本并称取质量,通过苏木精-伊红(H-E)染色观察脂肪组织和肝脏组织形态学的变化,采用实时荧光定量聚合酶链反应(RT-qPCR)分析脂肪组织和肝脏组织的产热基因、炎症基因,以及糖脂代谢相关基因的表达水平。结果·在肥胖治疗实验中,IF联合CL相较于单纯IF,可进一步减轻肥胖小鼠体质量并降低血糖(均P<0.05),减小eWAT和肝脏细胞内的脂滴(均P<0.05),促进eWAT与iWAT中产热基因解偶联蛋白1(uncoupling protein1,Ucp1)和细胞死亡诱导DFFA样效应蛋白α(cell death inducing DFFA like effector α,Cidea)的表达,上调eWAT与iWAT中脂肪酸氧化相关基因过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor α,Ppara)和烯酰辅酶A水合酶(enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase,Ehhadh)的表达(均P<0.05);与对照组相比,IF联合CL还可抑制eWAT和肝脏中炎症相关的基因表达(均P<0.05),促进肝脏糖代谢相关基因表达(均P<0.05),但与单纯IF相比差异无统计学意义。在肥胖预防实验中,IF联合CL相较于单纯IF,可进一步减小eWAT和iWAT细胞内的脂滴,促进eWAT与iWAT中Ucp1和Cidea的表达,上调eWAT与iWAT中Ppara和Ehhadh的表达(均P<0.05);与对照组相比,IF联合CL还可抵抗高脂饮食诱导的体质量增长,以及改善血糖(均P<0.05),并抑制肝脏脂肪酸氧化相关基因的表达水平(均P<0.05),但与单纯IF相比差异无统计学意义。结论·在肥胖治疗与预防模型中,与单纯IF相比,IF联合产热脂肪活化均可减少脂肪组织中脂肪沉积,促进白色脂肪中产热基因及脂肪酸氧化基因的表达;但两者对体质量和血糖的联合作用在肥胖治疗模型中优于单纯IF,在预防模型中则无明显优势。
中图分类号:
吴凯敏, 麻静, 赵旭赟. 间歇性禁食联合产热脂肪活化防治小鼠肥胖作用研究[J]. 上海交通大学学报(医学版), 2023, 43(9): 1131-1144.
WU Kaimin, MA Jing, ZHAO Xuyun. Combined effects of intermittent fasting and thermogenic fat activation on the treatment and prevention of obesity in mice[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(9): 1131-1144.
Gene | Forward sequence (5′→3′) | Reverse sequence (5′→3′) |
---|---|---|
Rplp0 | GAAACTGCTGCCTCACATCCG | GCTGGCACAGTGACCTCACACG |
Ccl2 | AGGTCCCTGTCATGCTTCTG | TCTGGACCCATTCCTTCTTG |
Ccl5 | TGCCCACGTCAAGGAGTATTT | TTCTCTGGGTTGGCACACACT |
Il-1b | GAAATGCCACCTTTTGACAGTG | TGGATGCTCTCATCAGGACAG |
Il-6 | AGTTGCCTTCTTGGGACTGA | TCCACGATTTCCCAGAGAAC |
Ucp1 | GGCATTCAGAGGCAAATCAGCT | CAATGAACACTGCCACACCTC |
Cidea | GCAGCCTGCAGGAACTTATCAGC | GATCATGAAATGCGTGTTGTCC |
leptin | AGCAGTGCCTATCCAGAA | TGCCAGAGTCTGGTCCATCT |
adiponectin | CAACTGAAGAGCTAGCTC | CTTAGGACCAAGAAGACCTG |
Ppara | AGAGCCCCATCTGTCCTCTC | ACTGGTAGTCTGCAAAACCAAA |
Pparg | CTGACCCAATGGTTGCTGAT | GGTGGAGATGCAGGTTCTAC |
Ehhadh | CAGATGAAGCACTCAAGCTTG | ACCTTGGCAATGGCTTCTGCA |
Hmgcs2 | GACATCAACTCCCTGTGCCTG | GATGTCAGTGTTGCCTGAATC |
Cidec | TCGACCTGTACAAGCTGAACCCT | AGGTGCCAAGCAGCATGTGACC |
Srebp1c | GATGTGCGAACTGGACACAG | CATAGGGGGCGTCAAACAG |
Fasn | GGAGGTGGTGATAGCCGGTAT | TGGGTAATCCATAGAGCCCAG |
Scd1 | GCTGGAGTACGTCTGGAGGAA | TCCCGAAGAGGCAGGTGTAG |
Dgat2 | GCGCTACTTCCGAGACTACTT | GGGCCTTATGCCAGGAAACT |
Gck | AGGAGGCCAGTGTAAAGATGT | CTCCCAGGTCTAAGGAGAGAAA |
Pfkl | TCCGCACCTACAACATCCAC | GGCTGGGATGACACACATGA |
Hk2 | TGATCGCCTGCTTATTCACGG | AACCGCCTAGAAATCTCCAGA |
Pkm | GCCGCCTGGACATTGACTC | CCATGAGAGAAATTCAGCCGAG |
Glut1 | TCAAACATGGAACCACCGCTA | AAGAGGCCGACAGAGAAGGAA |
Glut4 | GTGACTGGAACACTGGTCCTA | CCAGCCACGTTGCATTGTAG |
Pepck | CATATGCTGATCCTGGGCATAAC | CAAACTTCATCCAGGCAATGTC |
G6Pase | ACACCGACTACTACAGCAACAG | CCTCGAAAGATAGCAAGAGTAG |
表1 RT-qPCR引物序列
Tab 1 Primer sequences for RT-qPCR
Gene | Forward sequence (5′→3′) | Reverse sequence (5′→3′) |
---|---|---|
Rplp0 | GAAACTGCTGCCTCACATCCG | GCTGGCACAGTGACCTCACACG |
Ccl2 | AGGTCCCTGTCATGCTTCTG | TCTGGACCCATTCCTTCTTG |
Ccl5 | TGCCCACGTCAAGGAGTATTT | TTCTCTGGGTTGGCACACACT |
Il-1b | GAAATGCCACCTTTTGACAGTG | TGGATGCTCTCATCAGGACAG |
Il-6 | AGTTGCCTTCTTGGGACTGA | TCCACGATTTCCCAGAGAAC |
Ucp1 | GGCATTCAGAGGCAAATCAGCT | CAATGAACACTGCCACACCTC |
Cidea | GCAGCCTGCAGGAACTTATCAGC | GATCATGAAATGCGTGTTGTCC |
leptin | AGCAGTGCCTATCCAGAA | TGCCAGAGTCTGGTCCATCT |
adiponectin | CAACTGAAGAGCTAGCTC | CTTAGGACCAAGAAGACCTG |
Ppara | AGAGCCCCATCTGTCCTCTC | ACTGGTAGTCTGCAAAACCAAA |
Pparg | CTGACCCAATGGTTGCTGAT | GGTGGAGATGCAGGTTCTAC |
Ehhadh | CAGATGAAGCACTCAAGCTTG | ACCTTGGCAATGGCTTCTGCA |
Hmgcs2 | GACATCAACTCCCTGTGCCTG | GATGTCAGTGTTGCCTGAATC |
Cidec | TCGACCTGTACAAGCTGAACCCT | AGGTGCCAAGCAGCATGTGACC |
Srebp1c | GATGTGCGAACTGGACACAG | CATAGGGGGCGTCAAACAG |
Fasn | GGAGGTGGTGATAGCCGGTAT | TGGGTAATCCATAGAGCCCAG |
Scd1 | GCTGGAGTACGTCTGGAGGAA | TCCCGAAGAGGCAGGTGTAG |
Dgat2 | GCGCTACTTCCGAGACTACTT | GGGCCTTATGCCAGGAAACT |
Gck | AGGAGGCCAGTGTAAAGATGT | CTCCCAGGTCTAAGGAGAGAAA |
Pfkl | TCCGCACCTACAACATCCAC | GGCTGGGATGACACACATGA |
Hk2 | TGATCGCCTGCTTATTCACGG | AACCGCCTAGAAATCTCCAGA |
Pkm | GCCGCCTGGACATTGACTC | CCATGAGAGAAATTCAGCCGAG |
Glut1 | TCAAACATGGAACCACCGCTA | AAGAGGCCGACAGAGAAGGAA |
Glut4 | GTGACTGGAACACTGGTCCTA | CCAGCCACGTTGCATTGTAG |
Pepck | CATATGCTGATCCTGGGCATAAC | CAAACTTCATCCAGGCAATGTC |
G6Pase | ACACCGACTACTACAGCAACAG | CCTCGAAAGATAGCAAGAGTAG |
图1 间歇性禁食联合产热脂肪活化对肥胖小鼠体质量及血糖的影响Note: A. The schematic outline of the obesity treatment experiment. B. Accumulative food intake in four groups during intervention (38 d). C. Body weight in four groups during intervention. D. Blood glucose in four groups at the end of experiment. ①P=0.001, ②P=0.002, ④P=0.027, ⑥P=0.005, ⑦P=0.019, compared with the Ctrl1 group; ③P=0.002, compared with the CL1 group; ⑤P=0.049, ⑧P=0.010, compared with the IF1 group.
Fig 1 Effect of intermittent fasting combined with thermogenic fat activation on the body weight and blood glucose of obese mice
图2 间歇性禁食联合产热脂肪活化对肥胖小鼠脂肪和肝脏组织脂肪沉积的影响Note: A. The relative weight of eWAT, iWAT, BAT, and liver in the four groups. B. H-E staining of eWAT, iWAT, BAT, and liver sections in the four groups (×100). Scale bar=100 μm. C. The average diameters of the cells in eWAT, iWAT, BAT, and liver sections in the four groups. ①P=0.009, ②P=0.025, ③P=0.012, ④P=0.000, ⑦P=0.002, ⑨P=0.001, compared with the Ctrl1 group; ⑤P=0.000, ⑧P=0.020, ⑩P=0.010, compared with the CL1 group; ⑥P=0.000, compared with the IF1 group.
Fig 2 Effect of intermittent fasting combined with thermogenic fat activation on fat deposition in the fat and liver tissues of obese mice
图3 间歇性禁食联合产热脂肪活化对肥胖小鼠脂肪和肝脏组织炎症的影响Note: A. Inflammation genes in the eWAT analyzed by RT-qPCR. B. Inflammation genes in the liver analyzed by RT-qPCR. ①P=0.014, ②P=0.017, ③P=0.002, ④P=0.036, ⑤P=0.031. ⑥P=0.027, ⑦P=0.019, ⑧P=0.001, ⑨P=0.000, ⑩P=0.013, ?P=0.011, ?P=0.018, compared with the Ctrl1 group.
Fig 3 Effect of intermittent fasting combined with thermogenic fat activation on inflammation in the fat and liver tissues of obese mice
图4 间歇性禁食联合产热脂肪活化对肥胖小鼠白色脂肪组织代谢的影响Note: A. The expression of thermogenic genes in the eWAT analyzed by RT-qPCR. B. The expression of fatty acid oxidation genes in the eWAT analyzed by RT-qPCR. C. The expression of thermogenic genes in the iWAT analyzed by RT-qPCR. D. The expression of fatty acid oxidation genes in the iWAT analyzed by RT-qPCR. ①P=0.019, ②P=0.008, ④P=0.017, ⑤P=0.001, ⑧P=0.025, ⑨P=0.000, ⑩P=0.042, ?P=0.016, ?P=0.007, ?P=0.036, ?P=0.031, ?P=0.013, ?P=0.046, ?P=0.037, 22P=0.002, compared with the Ctrl1 group. ⑦P=0.004, ?P=0.037, 24P=0.003, compared with the CL1 group. ③P=0.010, ⑥P=0.002, ?P=0.003, ?P=0.049, 21P=0.037, 23P=0.000, 25P=0.001, compared with the IF1 group.
Fig 4 Effect of intermittent fasting combined with thermogenic fat activation on metabolism of white fat tissues in obese mice
图5 间歇性禁食联合产热脂肪活化对肥胖小鼠肝脏组织糖脂代谢的影响Note: A. The expression of fatty acid metabolism genes in the liver analyzed by RT-qPCR. B. The expression of gluconeogenesis and glycolysis genes in the liver analyzed by RT-qPCR. ①P=0.008, ②P=0.006, ③P=0.037, ④P=0.013. ⑤P=0.024, ⑥P=0.002, ⑦P=0.001, ⑧P=0.000, ⑨P=0.020, ⑩P=0.012, ?P=0.036, ?P=0.018, ?P=0.038, compared with the Ctrl1 group.
Fig 5 Effect of intermittent fasting combined with thermogenic fat activation on glucose and lipid metabolism in the liver tissue of obese mice
图6 间歇性禁食联合产热脂肪活化对高脂饮食引起的肥胖及血糖升高的预防作用Note: A. The schematic outline of the obesity prevention experiment. B. Accumulative food intake in four groups during intervention (124 d). C. Body weight in four groups during intervention. D. Blood glucose in four groups at the end of experiment. ①P=0.015, ③P=0.038, compared with the Ctrl2 group; ②P=0.023, ④P=0.045, compared with the CL2 group.
Fig 6 Preventive effect of intermittent fasting combined with thermogenic fat activation on high-fat diet-induced obesity and hyperglycemia
图7 间歇性禁食联合产热脂肪活化对高脂饮食诱导的脂肪和肝脏组织脂肪沉积的预防作用Note: A. The relative weight of eWAT, iWAT, BAT, and liver in the four groups. B. H-E staining of eWAT, iWAT, BAT and liver sections in the four groups (×100). Scale bar=100 μm. The arrow indicates the crown-like structure. C. The average diameters of the cells in eWAT, iWAT, BAT, and liver sections in the four groups. ①P=0.000, ②P=0.001, ③P=0.039, ④P=0.009, ⑤P=0.003, ⑥P=0.016, ⑦P=0.011, ⑧P=0.008, ⑨P=0.031, compared with the Ctrl2 group; ⑩P=0.001, ?P=0.016, compared with the IF2 group; ?P=0.000, ?P=0.005, compared with the CL2 group.
Fig 7 Preventive effect of intermittent fasting combined with thermogenic fat activation on high-fat diet-induced fat deposition in the fat and liver tissues
图8 间歇性禁食联合产热脂肪活化对高脂饮食诱导的脂肪和肝脏组织炎症的预防作用Note: A. Inflammation genes in the eWAT analyzed by RT-qPCR. B. Inflammation genes in the liver analyzed by RT-qPCR. ①P=0.024, ②P=0.028, ③P=0.010, ④P=0.040, ⑤P=0.039, compared with the Ctrl2 group.
Fig 8 Preventive effect of intermittent fasting combined with thermogenic fat activation on high-fat diet-induced inflammation in the fat and liver tissues
图9 间歇性禁食联合产热脂肪活化对高脂饮食小鼠白色脂肪组织代谢的影响Note: A. The expression of thermogenic genes in the eWAT analyzed by RT-qPCR. B. The expression of fatty acid oxidation genes in the eWAT analyzed by RT-qPCR. C. The expression of thermogenic genes in the iWAT analyzed by RT-qPCR. D. The expression of fatty acid oxidation genes in the iWAT analyzed by RT-qPCR. ①P=0.000, ④P=0.003, ⑥P=0.019, ⑦P=0.001, ⑧P=0.002, ⑨P=0.006, ?P=0.004, ?P=0.014, ?P=0.008, ?P=0.007, ?P=0.029, ?P=0.021, ?P=0.024, 21P=0.023, 22P=0.042, compared with the Ctrl2 group; ②P=0.001, ⑤P=0.000, ⑩P=0.006, ?P=0.020, ?P=0.041, ?P=0.005, 23P=0.010, 24P=0.003, compared with the IF2 group; ③P=0.012, compared with the CL2 group.
Fig 9 Effect of intermittent fasting combined with thermogenic fat activation on metabolism of white fat tissues in mice on a high-fat diet
图10 间歇性禁食联合产热脂肪活化对高脂饮食小鼠肝脏组织糖脂代谢的影响Note: A. The expression of fatty acid metabolism genes in the liver analyzed by RT-qPCR. B. The expression of gluconeogenesis and glycolysis genes in the liver analyzed by RT-qPCR. ①P=0.025, ②P=0.010, ③P=0.001, ④P=0.002, ⑤P=0.000, ⑥P=0.026, ⑦P=0.040, ⑧P=0.021, ⑨P=0.011, ⑩P=0.020, ?P=0.005, ?P=0.031, ?P=0.018, ?P=0.017, ?P=0.008, ?P=0.022, compared with the Ctrl2 group.
Fig 10 Effect of intermittent fasting combined with thermogenic fat activation on glucose and lipid metabolism in the liver tissue of mice on a high-fat diet
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