The therapeutic effects of a pentacyclic triterpene derivative, bardoxolone methyl, in preventing high-fat diet-induced obesity and associated neural, hepatic, cardiovascular, and renal complications

The prevalence of obesity is a growing problem since it significantly increases the risk of developing type 2 diabetes and associated complications of the brain, liver, heart, and kidneys. Therefore, there is an urgency to find novel therapies which can prevent obesity and the development of associated complications. This PhD project investigated whether selected pentacyclic triterpenes (oleanolic acid (OA), its isomer, ursolic acid (UA), and derivative, bardoxolone methyl (BM)) administered at 10 mg/kg daily in drinking water could prevent obesity in mice fed a chronic HF diet for 21 weeks. These compounds were chosen based on recent studies demonstrating that they have a number of anti-obese and anti-diabetes properties. In preliminary studies, BM prevented HF diet-induced body weight gain, while UA and OA had no effect. Following this, the molecular mechanisms underlying the ability of BM to prevent HF diet-induced obesity and associated complications were then examined. BM administration for 21 weeks prevented HF diet-induced increases in body weight, energy intake, plasma leptin, and peripheral fat (Chapter 2). Furthermore, in the mediobasal and paraventricular nuclei regions of the hypothalamus, BM treatment prevented HF diet-induced impairments of downstream leptin JAK2-Akt-FOXO1 signalling and increases in the inflammatory molecules, pJNK, TNFα and IL-6. These findings identify a potential novel neuropharmacological application for BM to prevent HF diet-induced obesity, hypothalamic inflammation and leptin resistance. BM administration also prevented HF diet-induced impairments in recognition memory (Chapter 3). Furthermore, in the hippocampus and prefrontal cortex (PFC), BM treatment prevented HF diet-induced decreases in downstream BDNF signalling molecules and increases in the inflammatory molecule, PTP1B. In summary, the findings from this chapter suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, and reducing inflammation in the PFC and hippocampus. BM treatment prevented HF diet-induced insulin resistance and hepatic steatosis in mice fed a HF diet (Chapter 4). Furthermore, in the livers of mice, BM prevented HF diet-induced impairments to hepatic IR-IRS-FOXO1 insulin signalling, ACOX-induced lipid metabolism, macrophage infiltration, and inflammation. These findings suggest that BM prevents HF dietinduced insulin resistance and the development of hepatic steatosis through modulation of molecules involved in insulin signalling, lipid metabolism, and inflammation in the liver. BM administration prevented HF diet-induced structural changes in the heart and kidneys (Chapter 5). Furthermore, in these tissues, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and TNFα gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Collectively, this thesis is novel in demonstrating that BM treatment prevents HF diet-induced obesity and associated leptin resistance, insulin resistance, cognitive deficits, and liver, kidney, and heart pathophysiologies in mice fed a HF diet for 21 weeks. These results suggest that these therapeutic effects were through anti-inflammatory mechanisms. Overall, these findings highlight BM as a potential novel therapeutic for preventing HF diet-induced obesity and a variety of associated complications

Survey and alignment of the synchrotron SIS18

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

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet

Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies

Bardoxolone methyl: a potential therapeutic for the prevention of anti-psychotic drug-induced obesity?

Abstract of a presentation

Is B-type natriuretic peptide a risk factor for heart failure in patients treated with bardoxolone methyl?

Letter to the Editor, comment on article entitled Risk Factors for Heart Failure in Patients With Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated With Bardoxolone Methyl by Chin et al in the Journal of Cardiac Failure

Comment on: Oleanolic acid co-administration alleviates ethanol-induced hepatic injury via Nrf-2 and ethanol-metabolizing modulation (sic) in rats

To the Editor: Alcohol induced hepatic oxidative stress and inflammation is known to cause liver injury. An increase in reactive oxidative species (ROS) from alcohol consumption leads to oxidative stress [1]. This can activate the inflammatory cytokines, IL-6 and TNF-α which promote liver injury. Both IL-6 and TNF-α are activated and transcribed by the inflammatory molecule, NFκB [2]. We read the interesting paper by Liu et al., entitled, “Oleanolic acid co-administration alleviates ethanol-induced hepatic injury via Nrf-2 and ethanol-metabolizing modulating in rats”, published in your journal recently [3]. The authors demonstrated that oleanolic acid can reduce hepatic injury by elevating Nrf-2 related antioxidants, reduce inflammation, and increase ethanol metabolism. We believe that the mechanism of modulating these signalling pathways could be important for understanding the protective effects of oleanolic acid

The endothelin pathway: a protective or detrimental target of bardoxolone methyl on cardiac function in patients with advanced chronic kidney disease?

Bardoxolone methyl has been reported to cause detrimental cardiovascular events in the terminated BEACON Phase III human clinical trial via modulation of the renal endothelin pathway. However, the effects of bardoxolone methyl administration on the endothelin pathway in the heart are unknown. Our purpose in this perspective is to highlight the distinctive opposing roles of the renal and heart endothelin pathway in cardiac function. Furthermore, we address the need for further investigation in order to determine if bardoxolone methyl has a protective role in cardiac function through the suppression of the endothelin pathway in the heart