Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet

• Published in: Chemico-biological interactions 2015-03, Vol.229, p.1-8
• Main Authors: Dinh, Chi H.L., Szabo, Alexander, Camer, Danielle, Yu, Yinghua, Wang, Hongqin, Huang, Xu-Feng
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - drug effects; Adipose tissue; Animals; Anti-Inflammatory Agents - therapeutic use; Antioxidants - therapeutic use; Bardoxolone methyl; Diet, High-Fat - adverse effects; Inflammation; Inflammation - immunology; Inflammation - metabolism; Inflammation - prevention & control; Intra-Abdominal Fat - drug effects; Intra-Abdominal Fat - immunology; Intra-Abdominal Fat - innervation; Intra-Abdominal Fat - metabolism; Macrophages - cytology; Macrophages - drug effects; Male; Mice; Mice, Inbred C57BL; Obesity; Obesity - immunology; Obesity - metabolism; Obesity - prevention & control; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - therapeutic use; Oxidative Stress - drug effects; Tumor Necrosis Factor-alpha - analysis; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2015.01.025

•Oral BARD administration prevents visceral fat deposition in high-fat diet.•Oral BARD prevents visceral fat macrophage infiltration and elevation of TNF-α.•Stress molecules in visceral fat are suppressed by BARD.•The energy expenditure molecules such as TH and UCP2 are increased by BARD.•Oral BARD provides a potential supplementary intervention in treating obesity. 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.