目的 探讨尿石素A对高脂饮食老龄小鼠白色脂肪棕色化的影响。方法 老龄小鼠18只随机分为对照组、高脂饮食组(HFD)和尿石素A干预组(UA),每组6只。UA组小鼠予尿石素A灌胃(吐温-80助溶),对照组和HFD组给予等剂量的吐温-80灌胃。实验结束后,记录各组小鼠的体质量和产热量,HE染色观察脂肪组织形态,qRT-PCR和Western blot检测棕色脂肪相关基因解偶联蛋白1(UCP1)、过氧化物酶体增殖体激活受体γ(PPARγ)与过氧化物酶体增殖体激活受体γ共激活因子-1α(PGC-1α)的表达。结果 与对照组相比,HFD组小鼠的体质量明显增加,日间产热量[(0.45±0.03)kcal/h vs.(0.62±0.05)kcal/h]和夜间产热量[(0.49±0.05)kcal/h vs.(0.73±0.06)kcal/h]均显著降低(P<0.05),脂肪细胞体积变大,UCP1、PPARγ与PGC-1α的转录表达降低(P<0.05)。而尿石素A干预降低高脂饮食小鼠的体质量,增加日间产热量[(0.57±0.03)kcal/h vs.(0.45±0.03)kcal/h]和夜间产热量[(0.69±0.07)kcal/h vs.(0.49±0.05)kcal/h],减小脂肪细胞体积,促进UCP1、PPARγ与PGC-1α的转录表达(P<0.05)。结论 尿石素A促进高脂饮食小鼠白色脂肪棕色化。
Abstract
Objective To investigate the effects of urolithin A on browning of white adipose in aged mice fed on a high-fat diet. Methods Eighteen aged mice were randomly divided into control group, high-fat diet (HFD) group and urolithin A administration group (UA), with 6 mice in each group. UA group was given urolithin A (Tween-80 aid solution), control group and HFD group were given the same dose of Tween-80. After the experiment, the body weight and heat production were detected, the morphology of adipocytes was observed by HE staining. qRT-PCR and Western blot were used to investigate mRNA and protein levels of uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Results Compared with the control group, the body weight of HFD group significantly increased, the heat production of the daytime[(0.45±0.03) kcal/h vs. (0.62±0.05) kcal/h] and nighttime[(0.49±0.05) kcal/h vs. (0.73±0.06) kcal/h] significantly decreased(P<0.05), and the cell size of white adipose tissue increased. Moreover, UCP1, PPARγ and PGC-1α expressions decreased (P<0.05). However, urolithin A intervention reduced the body weight of high-fat diet mice, increased daytime heat production [(0.57±0.03) kcal/h vs. (0.45±0.03) kcal/h] and nighttime heat production [(0.69±0.07) kcal/h vs. (0.49±0.05) kcal/h], and promoted the transcriptional expression of UCP1, PPARγ and PGC-1α expressions (P<0.05). Conclusions Urolithin A can promote the browning of white adipose tissue in aged mice fed on a high-fat diet.
关键词
尿石素A /
肥胖症 /
白色脂肪组织 /
棕色脂肪组织
Key words
urolithin A /
obesity /
white adipose tissue /
brown adipose tissue
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参考文献
[1] Zhu B, Li Y, Xiang L, et al. Alogliptin improves survival and health of mice on a high-fat diet[J]. Aging Cell, 2019,18(2):e12883.
[2] 柳 杨,田亚丽,古丽海夏·哈勒玛合拜,等. 尿石素A对2型糖尿病小鼠脂肪组织胰岛素抵抗的影响[J]. 中成药, 2020,42(7):1894-1898.
[3] Zhang Y, Jiang L, Su P, et al. Urolithin A suppresses tumor progression and induces autophagy in gastric cancer via the PI3K/Akt/mTOR pathway[J]. Drug Dev Res, 2022. DOI: 10.1002/ddr.22021.
[4] Mehra S, Srinivasan S, Singh S, et al. Urolithin A attenuates severity of chronic pancreatitis associated with continued alcohol intake by inhibiting PI3K/AKT/mTOR signaling[J]. Am J Physiol Gastrointest Liver Physiol, 2022,323(4):G375-G386.
[5] D′Amico D, Olmer M, Fouassier A M, et al. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis[J]. Aging Cell, 2022,21(8):e13662. .
[6] Cho S I, Jo E R, Song H. Urolithin A attenuates auditory cell senescence by activating mitophagy[J]. Sci Rep, 2022,12(1):7704.
[7] Xia B, Shi X C, Xie B C, et al. Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice[J]. PLoS Biol, 2020,18(3):e3000688.
[8] Huang J R, Zhang M H, Chen Y J, et al. Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation[J]. Acta Pharmacol Sin, 2022. DOI: 10.1038/s41401-022-00919-1.
[9] 张晓静,李 屹,朱 琳,等. 棕色脂肪细胞分化的分子调控及研究进展[J]. 武警医学, 2020,31(6):539-541.
[10] 何凯悦,徐晓丽,石凌峰,等. 髓源性生长因子对肥胖小鼠白色脂肪棕色化的影响[J]. 中华糖尿病杂志, 2022, 14(4):352-359.
[11] 杨文朋,吴方丽,田萧羽,等. 生长分化因子11对炎症微环境中兔BMSCs成骨分化的影响[J]. 北京口腔医学, 2022,30(1):21-24.
[12] Zhao W, Shi F, Guo Z, et al. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells[J]. Mol Carcinog, 2018,57(2):193-200.
[13] Boakye Y D, Groyer L, Heiss E H. An increased autophagic flux contributes to the anti-inflammatory potential of urolithin A in macrophages[J]. Biochim Biophys Acta Gen Subj, 2018,1862(1):61-70.
[14] Piwowarski J P, Kiss A K, Granica S, et al. Urolithins, gut microbiota-derived metabolites of ellagitannins, inhibit LPS-induced inflammation in RAW 264.7 murine macrophages[J]. Mol Nutr Food Res, 2015,59(11):2168-2177.
[15] Ryu D, Mouchiroud L, Andreux P A, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents[J]. Nat Med, 2016,22(8):879-888.
[16] Li S, Li Y, Xiang L, et al. Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults[J]. Metabolism, 2018,78:106-117.
[17] Ahmadian M, Suh J M, Hah N, et al. PPARγsignaling and metabolism: the good, the bad and the future[J]. Nat Med, 2013,19(5):557-566.
[18] Gao R, Chen W, Yan H, et al. PPARγ agonist rosiglitazone switches fuel preference to lipids in promoting thermogenesis under cold exposure in C57BL/6 mice[J]. J Proteomics, 2018,176:24-36.
[19] Zhang Z, Zhang H, Li B, et al. Berberine activates thermogenesis in white and brown adipose tissue[J]. Nat Commun, 2014,5:5493.
[20] Luo X, Li J, Zhang H, et al. Irisin promotes the browning of white adipocytes tissue by AMPKα1 signaling pathway[J]. Res Vet Sci, 2022,152:270-276.
[21] Zhu B, Li Y, Mei W, et al. Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism[J]. Vascul Pharmacol, 2019,115:55-63.
[22] Ko M S, Yun J Y, Baek I J, et al. Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice[J]. Autophagy, 2021,17(5):1205-1221.
[23] Yau W W, Singh B K, Lesmana R, et al. Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy[J]. Autophagy, 2019,15(1):131-150.
[24] Luan P, D′Amico D, Andreux P A, et al. Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy[J]. Sci Transl Med, 2021,13(588):319.