Adiponectin and postprandial inflammatory, oxidative and cardiovascular stress

Liza Phillips (2010). Adiponectin and postprandial inflammatory, oxidative and cardiovascular stress PhD Thesis, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, The University of Queensland.

       
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Author Liza Phillips
Thesis Title Adiponectin and postprandial inflammatory, oxidative and cardiovascular stress
School, Centre or Institute Diamantina Institute for Cancer, Immunology and Metabolic Medicine
Institution The University of Queensland
Publication date 2010-07
Thesis type PhD Thesis
Supervisor Professor John Prins
Associate Professor Jenny Martin
Associate Professor Jonathan Whitehead
Total pages 281
Total colour pages 6
Total black and white pages 275
Subjects 11 Medical and Health Sciences
Abstract/Summary The epidemic of obesity and type 2 diabetes (T2DM) places an enormous burden on health-care resources. The significant morbidity and mortality associated with these diseases includes a well characterised increased risk of cardiovascular disease. However, the precise links between obesity, metabolic dysfunction, including T2DM, and cardiovascular disease, remain unclear. Although traditionally viewed as an inert storage depot, adipose tissue has emerged as a dynamic endocrine organ, regulating energy balance, appetite, glucose homeostasis, immune function, coagulation and blood pressure through the effects of secreted factors termed adipokines. Pro-inflammatory adipokines include interleukin 6 (IL6), tumour necrosis factor α (TNFα), angiotensinogen, plasminogen activating inhibitor 1, resistin and leptin, while adiponectin is an anti-inflammatory, insulin-sensitising adipokine. A dysregulation of adipokines and the inflammatory response may be an important link between metabolic dysfunction and obesity. Inflammation appears to be as an important modulator of insulin resistance (IR) through inhibitory effects on insulin signaling. Although the inciting trigger remains unclear, adipose tissue, including resident bone-marrow derived macrophages, is the proposed source of these inflammatory mediators. Circulating monocytes and tissue-resident macrophages are also important in modulating systemic insulin sensitivity, while the proinflammatory transcription factor nuclear factor κB (NFκB) appears to play a role in orchestrating the inflammatory response. In addition it has been proposed that macronutrients themselves provoke an acute inflammatory response, and markers of oxidative stress are also elevated postprandially. Although the pathways through which this occurs have yet to be fully elucidated, nutritional fatty acids have recently been shown to induce inflammatory signaling in macrophages through ligand interaction with toll like receptor 4 (TLR4). Endothelial and vascular dysfunction have also been identified in the postprandial period; indeed atherosclerosis has long been proposed as a postprandial phenomenon. Postprandial inflammation and associated oxidative stress may therefore induce a metabolically unfavourable environment, in terms of both IR and associated cardiovascular dysfunction. High fat, high glucose loads appear to be particularly pathogenic. Such macronutrients may represent a greater risk to those with an impaired postprandial “anti-inflammatory” defence such that this population is predisposed to developing metabolic dysfunction. Adiponectin is an anti-inflammatory, anti-atherogenic, insulin-sensitising hormone. An abundant adipokine, adiponectin forms approximately 0.01% of total protein in the serum. Adiponectin is secreted in various multimeric structures; the metabolically important form appears to be the high molecular weight (HMW) multimer. The control of adiponectin secretion is incompletely understood and although produced primarily from adipose tissue, levels are reduced in obesity and T2DM. Increasing evidence suggests adiponectin may play a pivotal role in obesity-related conditions, including metabolic dysfunction and cardiovascular disease, highlighting the possibility for adiponectin replacement or manipulation as a treatment strategy. A central theme in this thesis explores the hypothesis that adiponectin, particularly HMW adiponectin is an important endogenous anti-inflammatory defence following a nutrient challenge and acts to modulate the postprandial inflammatory environment. This intrinsic anti-inflammatory response may mitigate the macronutrient induced pro-oxidant, pro-inflammatory milieu, in order to maintain insulin sensitivity and protect cardiovascular function. Dysregulation of this adipokine in the postprandial period in predisposed individuals, for example those with obesity and T2DM, may account for the metabolic dysfunction and increased cardiovascular risk seen in these subjects. This project will evaluate the inflammatory, metabolic and cardiovascular effects of a high-fat mixed meal in 3 cohorts of men: i) lean healthy ii) obese, non-diabetic and iii) subjects with T2DM. These cohorts will be studied for 6 hours following both a high-fat mixed test meal, and a water control. Adiponectin levels, including HMW multimers, will be evaluated postprandially. Systemic markers of oxidative stress and inflammatory mediators will be measured, in addition to evaluating the NFκB activation in peripheral blood mononuclear cells. Aortic stiffness will be evaluated in the postprandial period, documenting the cardiovascular effects following nutrient challenge. Changes in adiponectin levels postprandially will be evaluated and responses compared across cohorts. Changes in adiponectin will be correlated with inflammation, oxidative stress and cardiovascular function. Systematically characterising the postprandial state will allow confirmation of the available literature demonstrating proinflammatory effects of macronutrients, and extending this to enable comparisons between groups with increasing metabolic dysfunction. Identifying a dysregulation in adiponectin in the postprandial period in subjects with metabolic dysfunction will provide a platform for further investigation into the regulation of adiponectin secretion, including potential avenues for therapeutic manipulation.
Keyword postprandial dysmetabolism,
Oxidative stress
Inflammation
Adiponectin
Arterial stiffness
Augmentation Index
Additional Notes Colour: 39, 66, 68, 75, 79, 92 Landscape: 107-109, 112-114, 117-119, 138-140, 143-145, 148-150, 152-154, 157-159, 161-163, 167-169, 190

 
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Created: Sat, 11 Dec 2010, 06:44:54 EST by Dr Liza Phillips on behalf of Library - Information Access Service