Bardoxolone Methyl: A Targeted Antioxidant

et al. 2015

Nutrients

Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity.

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Section: Discussionsupporting

confidence: 93%

Bardoxolone Methyl Prevents Fat Deposition and Inflammation in Brown Adipose Tissue and Enhances Sympathetic Activity in Mice Fed a High-Fat Diet

et al. 2015

Nutrients

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“…BARD reduces nephritis in mice through suppression of AKT/ERK/NF- κ B signaling [ 71 ]. BARD induces anti-inflammatory and antioxidative effects in HFD mice in our study, which is consistent with the pharmacological function of BARD and its related compounds (oleanolic acid), which induce antioxidant anti-inflammatory properties via activating antioxidant response element- (ARE-) Kelch ECH associating protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) network [ 44 , 47 , 72 , 73 ]. A study on cardiac cells has shown that ERK activation suppresses Nrf2, leading to oxidative stress-induced insulin resistance in vitro and in vivo [ 74 ].…”

Section: Discussionsupporting

confidence: 88%

“…Bardoxolone methyl (BARD) is a synthetic pentacyclic triterpenoid compound derived from oleanolic acid. There is an increasing body of evidence showing that BARD modulates oxidative stress and inflammation via suppressing inflammatory signalling pathway and proinflammatory cytokines while activating anti-inflammatory antioxidant signalling pathway [ 44 – 46 ]. Moreover, BARD has been observed to benefit the immune system, brain, and peripheral tissues, including the kidneys, lungs, liver, colon, and white adipose tissue [ 47 – 51 ].…”

Section: Introductionmentioning

confidence: 99%

Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High‐Fat Diet Mice

The Scientific World Journal

et al. 2015

Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

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“…Although no significant difference in these proteins was observed between the HFD and LFD controls, the decreased expression induced by BARD indicated a positive role of BARD in preventing oxidative stress. There is evidence that BARD and the related compound oleanolic acid downregulate oxidative stress via the ARE-Keap1-Nrf2 signalling pathway [43,65,66]. In this study we provide evidence for an anti-obesity effect of BARD through antioxidant mechanism.…”

Section: Discussionmentioning

confidence: 62%

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

Chemico-Biological Interactions

Camer

et al. 2015