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

Abstract

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.

Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study)

“…25 Thus, improvements in glycemic control and lipid metabolism observed in preclinical studies with bardoxolone methyl may explain the reductions in body weight observed in humans. [26][27][28][29][30] Strengths of this trial include a randomized, placebocontrolled design and the measurement of GFR using the gold standard C in method in an interventional study. In addition, through strict handling procedures, we were able to control for diet, water intake, and physical conditions to minimize variability.…”

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

“…4, 9, 11, 32, 80 These outcomes observed during rodent and human studies utilizing CDDO derivatives, such as effects on fat deposition, weight loss, reduction of insulin resistance, and improved glucose tolerance, have been predicted as potential effects of modulating ghrelin signaling. 37–41 …”

Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice

“…HFD-induced fat accumulation in the colon wall and mucosa were reduced by BARD. We have previously observed the reducing effects of oral BARD on liver, white and brown adipose tissue in HFD-fed mice (Camer et al 2015a; Dinh et al 2015a; Dinh et al 2015b; Dinh et al 2015c). An increased lipid accumulation has been observed in the intestinal mucosal of HFD-induced and genetically-induced obese mice, as assessed by increased oil-red O staining of neutral fat and excess triacylglycerol (Douglass et al 2012).…”