Year

2015

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

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.

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