Obesity is a global health concern with management strategies encompassing bariatric surgery and anti-obesity drugs; however, concerns regarding complexities and side effects persist, driving research for more effective, low-risk strategies. The promotion of white adipose tissue (WAT) browning has emerged as a promising approach. Moreover, alisol B 23-acetate (AB23A) has demonstrated efficacy in addressing metabolic disorders, suggesting its potential as a therapeutic agent in obesity management. Therefore, in this study, we aimed to investigate the therapeutic potential of AB23A for mitigating obesity by regulating metabolic phenotypes and lipid distribution in mice fed a high-fat diet (HFD). An obesity mouse model was established by administration of an HFD. Glucose and insulin metabolism were assessed via glucose and insulin tolerance tests. Adipocyte size was determined using hematoxylin and eosin staining. The expression of browning markers in WAT was evaluated using Western blotting and quantitative real-time polymerase chain reaction. Metabolic cage monitoring involved the assessment of various parameters, including food and water intake, energy metabolism, respiratory exchange rates, and physical activity. Moreover, oil red O staining was used to evaluate intracellular lipid accumulation. A bioinformatic analysis tool for identifying the molecular mechanisms of traditional Chinese medicine was used to examine AB23A targets and associated signaling pathways. AB23A administration significantly reduced the weight of obese mice, decreased the mass of inguinal WAT, epididymal WAT, and perirenal adipose tissue, improved glucose and insulin metabolism, and reduced adipocyte size. Moreover, treatment with AB23A promoted the expression of browning markers in WAT, enhanced overall energy metabolism in mice, and had no discernible effect on food intake, water consumption, or physical activity. In 3T3-L1 cells, AB23A inhibited lipid accumulation, and both AB23A and rapamycin inhibited the mammalian target of rapamycin-sterol regulatory element-binding protein-1 (mTOR-SREBP1) signaling pathway. Furthermore, 3-isobutyl-1-methylxanthine, dexamethasone and insulin, at concentrations of 0.25 mmol/L, 0.25 μmol/L and 1 μg/mL, respectively, induced activation of the mTOR-SREBP1 signaling pathway, which was further strengthened by an mTOR activator MHY1485. Notably, MHY1485 reversed the beneficial effects of AB23A in 3T3-L1 cells. AB23A promoted WAT browning by inhibiting the mTOR-SREBP1 signaling pathway, offering a potential strategy to prevent obesity.

中文翻译：

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Alisol B 23-acetate 通过调节 mTOR-SREBP1 信号传导促进白色脂肪组织褐变以减轻高脂饮食诱导的肥胖


肥胖是一个全球性的健康问题，其管理策略包括减肥手术和抗肥胖药物;然而，对复杂性和副作用的担忧仍然存在，这推动了对更有效、低风险策略的研究。促进白色脂肪组织 （WAT） 褐变已成为一种很有前途的方法。此外，alisol B 23-acetate （AB23A） 已被证明在治疗代谢紊乱方面有效，表明其作为肥胖管理治疗剂的潜力。因此，在这项研究中，我们旨在通过调节高脂饮食 （HFD） 小鼠的代谢表型和脂质分布来研究 AB23A 在减轻肥胖方面的治疗潜力。通过施用 HFD 建立肥胖小鼠模型。通过葡萄糖和胰岛素耐量试验评估葡萄糖和胰岛素代谢。使用苏木精和伊红染色测定脂肪细胞大小。使用 Western blotting 和定量实时聚合酶链反应评估 WAT 中褐变标志物的表达。代谢笼监测涉及各种参数的评估，包括食物和水的摄入量、能量代谢、呼吸交换率和身体活动。此外，油红 O 染色用于评估细胞内脂质积累。使用用于鉴定中医分子机制的生物信息学分析工具来检查 AB23A 靶点和相关信号通路。AB23A 给药显着降低了肥胖小鼠的体重，减少了腹股沟 WAT 、附睾 WAT 和肾周脂肪组织的质量，改善了葡萄糖和胰岛素代谢，并减小了脂肪细胞大小。 此外，AB23A 处理促进了 WAT 中褐变标志物的表达，增强了小鼠的整体能量代谢，并且对食物摄入、饮水量或身体活动没有明显影响。在 3T3-L1 细胞中，AB23A 抑制脂质积累，AB23A 和雷帕霉素均抑制哺乳动物雷帕霉素-甾醇调节元件结合蛋白-1 （mTOR-SREBP1） 信号通路。此外，浓度分别为 0.25 mmol/L、0.25 μmol/L 和 1 μg/mL 的 3-异丁基-1-甲基黄嘌呤、地塞米松和胰岛素诱导 mTOR-SREBP1 信号通路的激活，该通路通过 mTOR 激活剂MHY1485进一步增强。值得注意的是，MHY1485 逆转了 AB23A 在 3T3-L1 细胞中的有益作用。AB23A 通过抑制 mTOR-SREBP1 信号通路促进 WAT 褐变，为预防肥胖提供了一种潜在的策略。