The aim of this study was to determine whether the atheroprotective phytochemical 23-hydroxy ursolic acid protects against diet-induced obesity and hyperglycemia by preventing nutrient stress-induced monocyte reprogramming. After a two week run-in period on a defined, phytochemical-free low-fat maintenance diet, 12-week old female C57BL/6J mice were either kept on the maintenance diet for additional 13 weeks or switched to either a high-calorie diet, a high-calorie diet supplemented with either 0.05% 23-hydroxy ursolic acid or a high-calorie diet supplemented with 0.2% 23-hydroxy ursolic acid. Dietary supplementation with 23-hydroxy ursolic acid reduced weight gain and adipose tissue mass, prevented hyperglycemia, hyperleptinemia and adipose tissue inflammation, and preserved glucose tolerance. 23-Hydroxy ursolic acid also preserved blood monocyte mitogen-activated protein kinase phosphatase-1 activity, a biomarker of monocyte health, and reduced macrophage content in the adipose tissue. Targeted gene profiling by qRT-PCR using custom-designed TaqMan® Array Cards revealed that dietary 23-hydroxy ursolic acid converts macrophages into a transcriptionally hyperactive phenotype with enhanced antioxidant defenses and anti-inflammatory potential. In conclusion, our findings show that dietary 23-hydroxy ursolic acid exerts both anti-obesogenic effects through multiple mechanisms. These include improving glucose tolerance, preventing hyperleptinemia, maintaining blood monocyte function, reducing recruitment of monocyte-derived macrophages into adipose tissues during nutrient stress, and converting these macrophages into an anti-inflammatory, potentially inflammation-resolving phenotype, all contributing to reduced adipose tissue inflammation. Our data suggest that 23-hydroxy ursolic acid may serve as an oral therapeutic and dietary supplement suited for patients at risk for obesity, impaired glucose tolerance and cardiovascular disease.

这项研究的目的是确定抗动脉粥样硬化的植物化学23-羟基熊果酸是否通过防止营养应激诱导的单核细胞重编程来预防饮食诱导的肥胖和高血糖症。在经过定义的无植物化学低脂维持饮食的两周磨合期后，将12周大的雌性C57BL / 6J小鼠继续维持饮食13周或改用高热量饮食，即补充有0.05％23-羟基熊果酸的高热量饮食或补充有0.2％23-羟基熊果酸的高热量饮食。膳食补充23-羟基熊果酸可减少体重增加和脂肪组织肿块，防止高血糖，高瘦素血症和脂肪组织发炎，并保持葡萄糖耐量。23-羟基熊果酸还保留了血液单核细胞促分裂原激活的蛋白激酶磷酸酶-1的活性，这是单核细胞健康的生物标志物，并减少了脂肪组织中巨噬细胞的含量。通过使用定制设计的TaqMan®Array Cards通过qRT-PCR进行靶向基因分析，发现膳食23-羟基熊果酸可将巨噬细胞转化为转录增强型表型，具有增强的抗氧化防御能力和抗炎潜力。总之，我们的发现表明，饮食中的23-羟基熊果酸通过多种机制发挥抗肥胖作用。这些措施包括改善葡萄糖耐量，预防高瘦素血症，维持血液单核细胞功能，减少营养胁迫期间单核细胞衍生的巨噬细胞向脂肪组织的募集以及将这些巨噬细胞转化为抗炎药，潜在的消炎表型，均有助于减少脂肪组织的炎症。我们的数据表明，23-羟基熊果酸可以作为口服治疗剂和饮食补充剂，适合有肥胖，糖耐量受损和心血管疾病风险的患者。