This thesis investigated the differential effects of α-tocopherol, tocotrienols, and renin-angiotensin system (RAS) inhibitors on the pathophysiology of metabolic syndrome using a rat model of dietinduced obesity that mimics the metabolic syndrome in humans. Metabolic syndrome is associated with obesity, insulin resistance, hypertension and cardiovascular disease. The increasing prevalence of the metabolic syndrome and the progression of the associated diseases have made metabolic syndrome an important public health concern. Lifestyle (weight loss and exercise) and dietary modification (balanced diet and functional food) have been perceived as the first-line interventions in metabolic syndrome. In addition, pharmacological therapies that reduce the incidence of metabolic syndrome have the significant potential to lower the risks.
Metabolic syndrome is a complex multifactorial disorder with inflammation and oxidative stress altering the hormonal control and causing pathophysiogical changes in the body. Inflammation can be classified as acute and chronic. Acute inflammation is an immediate response of the body to ward off harmful pathogens. However, when inflammation persists for a longer period, progressive changes in the type of the cells at the site of damage occur and lead to chronic inflammation. Obesity is regarded as low grade chronic inflammation. Hence, anti-inflammatory agents might have potential for the prevention and treatment of metabolic syndrome. In addition, RAS, an endocrine system which traditionally was thought to only modulate the haemodynamics of the body has recently been implicated in obesity, diabetes and liver fibrosis. Inhibition of the RAS may ameliorate pathological changes in metabolic syndrome. Although metabolic syndrome is caused by dysregulation of inflammatory pathways, oxidative stress and altered RAS, current clinical management of treating metabolic syndrome is primarily treating type 2 diabetes and cardiovascular events using drugs that modulate a single target which very often leads to polypharmacy. However, recent progression on metabolic syndrome suggests two major closely-related causes of the metabolic syndrome as abdominal obesity and insulin resistance. Treatment of the metabolic syndrome should address the main underlying metabolic abnormalities and coexistent risk factors including obesity, insulin resistance, cardiovascular and liver dysfunction, rather than treating each risk factor separately. Therefore, there is urgent need to identify of agents which target multiple sites to manage metabolic syndrome.
Hence, I investigated the effects of bioactive compounds known to have antioxidant and antiinflammatory responses, including tocotrienol-rich fractions (TRF), a mixture of tocotrienols with α-tocopherol and the inhibition of RAS using angiotensin-converting enzyme inhibitor (ACE inhibitor, perindopril) and angiotensin II type 1 receptor antagonist (AT1R antagonist, candesartan)in this rat model of human obesity in response to adiposity, metabolic function, cardiovascular, liver structure and function. Tocotrienols and α-tocopherol have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. Here in this study, TRF provided cardiovascular protection by reducing the cardiovascular stiffness and augmented the ventricular function, improved glucose and insulin tolerance, and enhanced liver function in obese rats without alteration to the adiposity. A key change that may improve cellular survival is the reduced infiltration of inflammatory cells in the heart and liver. However, TRF is a mixture of tocotrienols with α-tocopherol hence it was difficult to point out the effects of each homologues in metabolic syndrome. With the aim of understanding the individual effects of these homologues in TRF, I proceeded further to investigate the differential effects of α-tocopherol and α-, δ- and γ-tocotrienols in regulation of metabolic syndrome. This study showed that the biological activities of α-tocopherol and α-tocotrienol are different from γ- and δ-tocotrienols in metabolic syndrome. While α-tocopherol, α- γ- and δ- tocotrienols improved liver structure and function, only γ- and δ-tocotrienols provided cardiovascular protection with reduced cardiovascular stiffness, blood pressure and improved systolic function besides attenuating obesity. In addition, only δ-tocotrienol improved glucose and insulin tolerance. Chronic oral treatment with tocotrienols successfully delivered tocotrienols to the vital organs despite low or no detection of tocotrienols in plasma. The therapeutic effects of tocotrienols may be associated with the reduction of proinflammatory microenvironments in obese rats and the involvement of the autonomic nervous system. The biological activities of α-, γ- and δ- tocotrienols are different from each other. With their distribution in vital organs and the therapeutic effect of tocotrienols in these organs, tocotrienols should be considered as biologically active vitamin E.
The current literature demonstrates involvement of RAS in fat mass development in transgenic models. These however do not represent the aetiology of obesity in humans with metabolic syndrome which is largely diet-induced. Also, the differences of RAS inhibition in obese and nonobese condition were not addressed in previous studies. In this study, I showed the effect of ACE inhibitor (perindopril) and AT1R antagonist (candesartan) using a reversal protocol in diet-induced obese rats which mimic the metabolic syndrome in humans. The underlying mechanism of RAS in pathophysiology of metabolic syndrome may involve inflammation with reactive oxygen species providing the oxidative stress milieu to initiate inflammation. RAS inhibition reduced the accumulation of adipose tissue and inflammatory cells infiltration in the cardiac and liver. This helped decrease the proinflammatory milieu, ameliorated impaired glucose and insulin tolerance,enhanced cardiovascular and liver structure and functions. The preliminary data suggested pleiotropic effects of AT1 antagonism and ACE inhibition in managing metabolic syndrome but further studies are warranted.
The work in this thesis provided evidence for the role of proinflammatory microenvironments in the pathophysiology of metabolic syndrome and the pharmaceutical and nutraceutical approaches in managing metabolic syndrome. Tocotrienols and inhibition of RAS with the ACE inhibitor and AT1 receptor antagonist decreased the oxidative stress milieu and proinflammatory microenvironments. This minimised the impact of metabolic syndrome on cardiovascular, liver function and glucose metabolism, providing possible multiple targets approach with combined pharmaceutical and nutraceutical therapy in managing metabolic syndrome.