Oleanolic acid inhibits diet-induced adiposity through blocking neovascularization and macrophage accumulation involving Delta-like 4-Notch 1-nuclear factor-κB signaling.

BACKGROUND/OBJECTIVES: Obesity is a major risk factor in the pathogenesis of cardiometabolic disorders. Most of these obesity-related disorders are closely associated with vascular dysfunctions. Due to the increase of fat mass in obesity, oxygen deficiency is induced, thus developing adipose tissue vascularization. Additionally, local hypoxia generates adipokine expression and proinflammatory macrophage recruitment. This study was conducted to test efficiency of oleanolic acid on angiogenesis and proinflammation in diet-induced obese mice model.

MATERIALS/METHODS: C57BL/6 mice were fed 10% fat or 45% fat and treated with 10 mg/kg oleanolic acid as gavage for 20 weeks. Body weight, adipose tissue weight, and adipocyte morphology were evaluated. Angiogenesis-related signaling pathways, oxidative stress, and inflammatory markers in adipose tissue were assessed using molecular and histological analyses.

RESULTS: Oleanolic acid decreased body weight and fat tissue weight of obese mice. Oleanolic acid inhibited diet-induced adipocyte expansion and adiposity. This natural compound reduced adipose tissue angiogenesis of obese mice through blockade of hypoxia-inducible factors 1α-vascular endothelial growth factor receptor-2 signaling and Ang-Tie2 axis. The reactive oxygen species production was reduced by oleanolic acid in fatty adipose tissues. Oleanolic acid inhibited macrophage infiltration into the adipose tissues of obese mice. Oral administration of oleanolic acid blocked Delta-like 4 (Dll4)-Notch 1-nuclear factor (NF)-κB signaling axis in adipose tissues of high fat-fed mice.

CONCLUSION: These results indicate that oleanolic acid is a potential therapeutic strategy to alleviate diet-induced adiposity at least by blocking Dll4-Notch-NF-κB signaling-associated neovascularization and macrophage inflammation in adipose tissues.