醉茄素A通过诱导白色脂肪组织褐变抵御高脂饮食诱导的肥胖

郭冰冰; 王炳蔚; 苏志洁; 张辰雨; 赵淼; 王俊博; 郑瑞茂

doi:10.16098/j.issn.0529-1356.2020.04.017

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解剖学报 ›› 2020, Vol. 51 ›› Issue (4) : 570-575. DOI: 10.16098/j.issn.0529-1356.2020.04.017

组织学胚胎学发育生物学

醉茄素A通过诱导白色脂肪组织褐变抵御高脂饮食诱导的肥胖

郭冰冰王炳蔚苏志洁张辰雨赵淼王俊博郑瑞茂*

作者信息 +

Withaferin A protecting against high fat diet induced obesity by inducing white adipose tissue browning

GUO Bing-bing WANG Bing-wei SU Zhi-jie ZHANG Chen-yu ZHAO Miao WANG Jun-bo ZHENG Rui-mao*

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文章历史 +

摘要

目的探索醉茄素A对高脂饮食诱导肥胖的抵抗作用及其作用机制。方法 8周龄C57BL/6 J小鼠分为醉茄素A组和对照组，每组10只，高脂饮食（HFD）饲养，分别给予醉茄素A或对照溶剂DMSO腹腔注射，每天测量小鼠体重及摄食量。1周后取材，称量小鼠腹股沟白色脂肪（iWAT）、附睾白色脂肪（eWAT）、腹膜后白色脂肪（rWAT）和肩胛间棕色脂肪（BAT）的重量；取iWAT检测褐变相关因子表达水平；HE染色观察iWAT细胞形态变化。结果醉茄素A组小鼠的体重和各部位脂肪组织重量均显著低于对照组，摄食量无明显变化；Real-time PCR显示，醉茄素A组小鼠iWAT中褐变相关基因表达水平显著提高；Western blotting结果表明，醉茄素A组小鼠iWAT中解耦联蛋白1（UCP1）和过氧化物酶体增殖体激活受体γ共激活因子1α（PGC1α）表达明显增加；HE染色与免疫荧光结果显示，醉茄素A组小鼠腹股沟白色脂肪细胞呈现典型褐变特征，如脂肪细胞多腔室化。结论醉茄素A可能通过诱导小鼠白色脂肪组织褐变抵御高脂饮食诱导的肥胖。

Abstract

Objective To investigate the protective effect of withaferin A (WA) against high fat diet induced obesity and its associated mechanism. Methods C57BL/6 J mice at 8-week of age were divided into two groups. The mice were fed with high fat diet (HFD) and were given an intraperitoneal injection of WA or DMSO (solvent control). The body weight and food intake of the mice were monitored. One week later, inguinal white adipose tissue (iWAT), interscapular brown adipose tissue (BAT), epididymal white adipose tissue (eWAT) and retroperitoneal white adipose tissue (rWAT) were collected and weighed. Expression levels of the genes associated with white adipose browning were detected in iWAT. HE staining was applied to observe the morphological changes of iWAT. Results The data showed that body weight and fat weight in WA group were significantly lower than those in the control group, and the food intake was not changed significantly. Real-time PCR analysis showed that the expression level of browning related genes in iWAT of the WA group was significantly increased. The result from Western blotting analysis showed that the protein levels of uncoupling protein 1(UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC1α) increased significantly in iWAT of the WA group. The typical morphological change of adipose browning, such as the multilocular adipocytes was observed in inguinal white adipose tissue of the mice treated with WA by using HE staining and mmunofluorescence assay. Conclusion Taken together, these observations indicate that withaferin A can protect the mice from high fat diet induced obesity by promoting white adipose tissue browning.

导出引用

郭冰冰王炳蔚苏志洁张辰雨赵淼王俊博郑瑞茂. 醉茄素A通过诱导白色脂肪组织褐变抵御高脂饮食诱导的肥胖[J]. 解剖学报. 2020, 51(4): 570-575 https://doi.org/10.16098/j.issn.0529-1356.2020.04.017

GUO Bing-bing WANG Bing-wei SU Zhi-jie ZHANG Chen-yu ZHAO Miao WANG Jun-bo ZHENG Rui-mao. Withaferin A protecting against high fat diet induced obesity by inducing white adipose tissue browning[J]. Acta Anatomica Sinica. 2020, 51(4): 570-575 https://doi.org/10.16098/j.issn.0529-1356.2020.04.017

中图分类号： R723.14

参考文献

［1］ Ghaben AL, Scherer PE. Adipogenesis and metabolic health［J］. Nat Rev Mol Cell Biol, 2019, 20(4): 242-258.

［2］ Andersen CJ, Murphy KE, Fernandez ML. Impact of obesity and metabolic syndrome on immunity［J］. Adv Nutr, 2016, 7(1): 66-75.

［3］ Phillips CM. Metabolically healthy obesity: personalised and public health implications［J］. Trends Endocrinol Metab, 2016, 27(4): 189-191.

［4］ Lee J, Liu J, Feng X, et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice［J］. Nat Med, 2016, 22(9): 1023-1032.

［5］ Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease［J］. Nature, 2008, 454(7203): 463-469.

［6］ Petrovic N, Walden TB, Shabalina IG, et al. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes［J］. J Biol Chem, 2010, 285(10): 7153-7164.

［7］ Ohno H, Shinoda K, Spiegelman BM, et al. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein［J］. Cell Metab, 2012, 15(3): 395-404.

［8］ Martinez-Demena R, Calvo RM, Garcia L, et al. Effect of glucocorticoids on the activity, expression and proximal promoter of type Ⅱ deiodinase in rat brown adipocytes［J］. Mol Cell Endocrinol, 2016, 428: 58-67.

［9］ Choi YS, Lee KU, Pak YK. Regulation of mitochondrial transcription factor A expression by high glucose［J］. Ann N Y Acad Sci, 2004, 1011: 69-77.

［10］ Mccarty MF. Up-regulation of PPARgamma coactivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity［J］. Med Hypotheses, 2005, 64(2): 399-407.

［11］ Farmer SR. Brown fat and skeletal muscle: unlikely cousins ［J］ ? Cell, 2008, 134(5): 726-727.

［12］ Schulz TJ, Huang TL, Tran TT, et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat［J］. Proc Natl Acad Sci U S A, 2011, 108(1): 143-148.

［13］ Wu J, Bostrom P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human［J］. Cell, 2012, 150(2): 366-376.

［14］ Betz M J, Enerback S. Human brown adipose tissue: what we have learned so far［J］. Diabetes, 2015, 64(7): 2352-2360.

［15］ Cypess AM, White AP, Vernochet C, et al.Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat［J］. Nat Med, 2013, 19(5): 635-639.

［16］ Schrauwen P, Van Marken Lichtenbelt WD, Spiegelman BM. The future of brown adipose tissues in the treatment of type 2 diabetes［J］. Diabetologia, 2015, 58(8): 1704-1707.

［17］ Royston KJ, Udayakumar N, Lewis K, et al. A novel combination of withaferin a and sulforaphane inhibits epigenetic machinery, cellular viability and induces apoptosis of breast cancer cells［J］. Int J Mol Sci, 2017, 18(5): 1092.

［18］ Lee W, Kim TH, Ku SK, et al. Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models［J］. Toxicol Appl Pharmacol, 2012, 262(1): 91-98.

［19］ Challa AA, Vukmirovic M, Blackmon J, et al. Withafterin A reduces type Ⅰ collagen expression in vitro and inhibits development of myocardial fibrosis in vivo［J］. PLoS One, 2012, 7(8): e42989.

［20］ Marlow MM, Shah SS, Veliz EA, et al. Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives［J］. J Nat Med, 2017, 71(1): 16-26.

［21］ Oh JH, Kwon TK. Withaferin A inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules by inactivation of Akt and NF-kappaB in human pulmonary epithelial cells［J］. Int Immunopharmacol, 2009, 9(5): 614-619.

［22］ Li AX, Sun M, Li X. Withaferin-A induces apoptosis in osteosarcoma U2OS cell line via generation of ROS and disruption of mitochondrial membrane potential［J］. Eur Rev Med Pharmacol Sci, 2017, 21(6): 1368-1374.

［23］ Sorelle JA, Itoh T, Peng H, et al. Withaferin A inhibits pro-inflammatory cytokineinduced damage to islets in culture and following transplantation［J］. Diabetologia, 2013, 56(4): 814-824.

［24］ Patel P, Julien JP, Kriz J. Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis［J］. Neurotherapeutics, 2015, 12(1): 217-233.

［25］ Jadeja RN, Urrunaga NH, Dash S, et al. Withaferin-A reduces acetaminophen-induced liver injury in mice［J］. Biochem Pharmacol, 2015, 97(1): 122-132.

［26］ Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with ashwagandha root extract: a double-blind, randomized, placebo-controlled trial［J］. J Evid Based Complementary Altern Med, 2017, 22(1): 96-106.