Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, NSW 2522, Australia.
Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, NSW 2522, Australia; ANSTO LifeSciences, Australian Nuclear Science and Technology Organisation, NSW 2234, Australia.
Chem Biol Interact. 2015 Mar 5;229:1-8. doi: 10.1016/j.cbi.2015.01.025. Epub 2015 Jan 28.
Key features of diet-induced obesity are visceral fat deposition, macrophage infiltration and inflammation that can lead to metabolic disorders. This study examined the effects of bardoxolone methyl (BARD) in preventing obesity and inflammation in the visceral fat of mice fed high-fat diet. Male C57BL/6J mice were fed a high-fat diet (HFD), a low-fat diet (LFD, i.e., lab chow diet) or a high-fat diet supplemented with BARD (HFD/BARD) for 21weeks. BARD at a dosage of 10mg/kg body weight was administered orally in drinking water. Histology, immunohistochemistry and Western blot were used for the analysis of epididymal adipose tissue. Morphological results demonstrated that HFD fed mice treated with BARD had smaller adipocytes and fewer macrophages present in epididymal adipose tissue than the HFD group. Furthermore, BARD administration reduced the inflammatory profile in this tissue by increasing the expression of nuclear factor of kappa-light-polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) protein and decreasing the protein expression of tumour necrosis factor alpha (TNF-α). BARD also prevented oxidative stress reflected by a reduction in stress activated proteins, including signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). BARD administration activated the sympathetic nervous system in epididymal adipose tissue assessed by the increased synthesis of tyrosine hydroxylase (TH) and uncoupling protein 2 (UCP2). The expression of inflammatory and sympathetic nervous system proteins in BARD mice fed a HFD was equivalent to that of the LFD control mice, indicating the anti-inflammatory and anti-obesity properties of this drug. In conclusion, the oral administration of BARD in HFD mice prevented fat deposition, inflammation and oxidative stress, and improved sympathetic activity in visceral fat. This study suggests a potential therapeutic role of BARD in preventing the development of obesity.
饮食诱导肥胖的主要特征是内脏脂肪沉积、巨噬细胞浸润和炎症，这些会导致代谢紊乱。本研究旨在探讨 bardoxolone 甲基（BARD）在预防高脂肪饮食喂养的小鼠内脏脂肪肥胖和炎症中的作用。雄性 C57BL/6J 小鼠喂食高脂肪饮食（HFD）、低脂饮食（LFD，即实验室饲料饮食）或高脂肪饮食补充 BARD（HFD/BARD）21 周。BARD 以 10mg/kg 体重的剂量通过饮用水进行口服给药。组织学、免疫组织化学和 Western blot 用于分析附睾脂肪组织。形态学结果表明，与 HFD 组相比，用 BARD 处理的 HFD 喂养小鼠的附睾脂肪组织中脂肪细胞较小，巨噬细胞较少。此外，BARD 给药通过增加核因子κ轻肽基因增强子 B 细胞抑制剂，α（IκB-α）蛋白的表达和减少肿瘤坏死因子α（TNF-α）的蛋白表达来减少该组织中的炎症表型。BARD 还通过减少应激激活蛋白，包括信号转导和转录激活因子 3（STAT3）、蛋白激酶 B（Akt）、细胞外信号调节激酶（ERK）和 c-Jun N-末端激酶（JNK），来预防氧化应激。BARD 给药通过增加酪氨酸羟化酶（TH）和解偶联蛋白 2（UCP2）的合成来激活附睾脂肪组织中的交感神经系统。在 HFD 喂养的 BARD 小鼠中，炎症和交感神经系统蛋白的表达与 LFD 对照组相当，表明该药物具有抗炎和抗肥胖作用。总之，BARD 在 HFD 小鼠中的口服给药可预防脂肪沉积、炎症和氧化应激，并改善内脏脂肪中的交感神经活性。这项研究表明 BARD 在预防肥胖发展方面具有潜在的治疗作用。
