间歇性禁食联合产热脂肪活化防治小鼠肥胖作用研究

doi:10.3969/j.issn.1674-8115.2023.09.007

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

间歇性禁食联合产热脂肪活化防治小鼠肥胖作用研究

吴凯敏¹(), 麻静¹(), 赵旭赟²()

^1.上海交通大学医学院附属仁济医院内分泌代谢病科，上海 200127
^2.上海交通大学基础医学院生物化学与分子细胞生物学系，上海 200025

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，电子信箱：majing3436@163.com。
赵旭赟，电子信箱：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:
上海交通大学医学院“双百人”项目(20181807)

Combined effects of intermittent fasting and thermogenic fat activation on the treatment and prevention of obesity in mice

WU Kaimin¹(), MA Jing¹(), ZHAO Xuyun²()

^1.Department of Endocrinology and Metabolism, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
^2.Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China

Received:2023-04-06 Accepted:2023-09-03 Online:2023-09-28 Published:2023-09-28
Contact: MA Jing, E-mail: majing3436@163.com. #Co-responding authors.
ZHAO Xuyun, E-mail: xuyunzhao@shsmu.edu.cn
Supported by:
“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20181807)

摘要/Abstract

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。

关键词: 间歇性禁食, 产热脂肪活化, 肥胖, 治疗, 预防

Abstract:

Objective ·To investigate the effects of intermittent fasting (IF) combined with thermogenic fat activation on the treatment and prevention of obesity in mice. Methods ·Male C57BL/6J mice aged 8 weeks were fed by high-fat diet for 4 months and then used as obesity treatment models. The prevention model was conducted on male and 8-week-old C57BL/6J mice. High-fat diet-induced obese mice and normal mice were respectively assigned into four groups: control group, alternate-day intraperitoneal CL316243 (β3-adrenergic receptor agonist,CL) injection group, IF group, and IF combined with alternate-day intraperitoneal CL injection group. Obesity treatment experimental mice and obesity prevention experimental mice were intervened for 38 d and 124 d, respectively, and they were all fed with high-fat diet during the intervention. The food intake and body weight were measured every two days. The blood glucose was measured at the end of the experiments. The brown adipose tissues (BAT), inguinal white adipose tissues (iWAT), epididymal white adipose tissues (eWAT), and livers were collected and weighed after the mice were sacrificed. The effect of IF combined with CL on morphologic changes was investigated by hematoxylin-eosin (H-E) staining. The expression levels of the genes related to thermogenesis, inflammation, and glucose and lipid metabolisms in the livers and adipose tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Results ·In the treatment model, compared with IF alone, IF combined with CL further reduced the body weight and blood glucose of obese mice (P<0.05), reduced the lipid droplet size in the eWAT cells and the liver cells (P<0.05), promoted the expression levels of the thermogenic genes uncoupling protein 1 (Ucp1) and cell death inducing DFFA like effector α (Cidea) in the eWAT and the iWAT, and up-regulated the expressions of the fatty acid oxidation related genes in the eWAT and the iWAT, i.e., peroxisome proliferator-activated receptor α (Ppara) and enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (Ehhadh) (P<0.05). IF combined with CL also inhibited the expressions of inflammation-related genes in the eWAT and the liver (P<0.05) and promoted the expressions of glucose metabolism-related genes in the liver compared with the control group (P<0.05), but there were no significant differences compared with IF alone. In the prevention model, compared with IF alone, IF combined with CL further reduced the lipid droplet size in the eWAT cells and the iWAT cells, promoted the expression levels of Ucp1 and Cidea in the eWAT and the iWAT, and up-regulated the expression of Ppara and Ehhadh in the eWAT and the iWAT (P<0.05). IF combined with CL also resisted the weight gain induced by high-fat diet, improved blood glucose (P<0.05), and inhibited the expression levels of fatty acid oxidation-related genes in the liver compared with the control group (P<0.05), but there were no significant differences compared with IF alone. Conclusion ·Both in the obesity treatment and prevention models, IF combined with thermogenic fat activation can reduce lipidosis in the adipose tissue and promote the expression of thermogenic genes and fatty acid oxidation genes in the white adipose tissue compared with IF alone; however, the combined effects of them on body weight and blood glucose are superior to IF in the obesity treatment model, but not in the prevention model.

Key words: intermittent fasting, thermogenic fat activation, obesity, treatment, prevention

中图分类号:

R589.2

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.

图/表 11

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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间歇性禁食联合产热脂肪活化防治小鼠肥胖作用研究

Combined effects of intermittent fasting and thermogenic fat activation on the treatment and prevention of obesity in mice

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