Modulation of the immune sytem in the metabolic syndrome

Obesity is a medical condition in which excessive fat storage occurs in tissues and is closely associated with metabolic dysfunction, which is a major cause of morbidity and mortality in most societies. The clinical features of obesity, especially centrally distributed abdominal fat, combined with hyperglycemia, hyperlipidemia and hypertension, form the basis for varying definitions of the metabolic syndrome. The metabolic syndrome increases risk of developing cardiovascular disease, insulin resistance and/or type II diabetes mellitus, which are a major public health issue in both developed and developing countries. Lifestyle changes, such as an excessive caloric intake, are indicated as one of the most important factors in initiating obesity and associated metabolic and cardiovascular disorders. Recent studies suggest that excessive macronutrient intake promotes cross-talk between metabolic and immune pathways leading to obesity and the associated metabolic dysfunction. A better molecular understanding of these biochemical mechanisms that underpin adiposity and metabolic dysfunction has the potential to uncover new therapeutic strategies for the treatment of obesity and the metabolic syndrome. This thesis has characterised the changes in adiposity, metabolic and cardiovascular function in rats fed excess macronutrients in the form of high fat, high carbohydrate diets. The use of selective pharmacological tools and natural compounds which can modulate the immune system has allowed an improved understanding of the biochemical mechanisms and the evaluation of novel therapeutic targets and strategies to combat adiposity and the metabolic syndrome. The studies in this thesis suggest that the endocrine and immune systems are indeed connected through autocrine and paracrine, immune and lipid signalling in sophisticated networks that are only now beginning to become unravelled. Excessive nutrient intake promotes adiposity, altering adipocyte function and immune cell distribution, both of which appear to trigger metabolic dysfunction. Drug discovery targets for obesity and metabolic dysfunction may include the synthetic pathways of various inflammatory proteins and lipid mediators including the complement proteins, phospholipase A2, soluble epoxide hydrolases and lysine deacetylases. The subsequent modulation of the enzymes and receptors of these synthetic pathways through either receptor antagonists or agonists or enzyme inhibitors may provide new therapeutic approaches to obesity and the associated metabolic and cardiovascular dysfunction. Further, since dietary choice remains the basis for maintaining a healthy lifestyle and well-being, especially relating to metabolic and cardiovascular disease, this thesis has investigated the potential of natural compounds found in foods which can modulate the immune system as an effective therapeutic strategy. Compounds such as wheat germ extract (Avemar), vitamin E & α-lipoic acid and green tea attenuated the symptoms of metabolic syndrome, type II diabetes mellitus and the associated cardiovascular changes in rats. These studies suggest that functional foods could be a potential therapeutic strategy to combat cardiovascular disease, insulin resistance and/or type II diabetes mellitus in humans