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.