Fractures are a major public health concern and there is an urgent need to identify high-risk individuals. This study used novel approaches in bone imaging to characterize optimal skeletal development in girls and enhance our understanding of the structural and functional deficits that contribute to skeletal fragility and fracture risk during growth. The findings indicate that fracture in girls is associated with lower trabecular bone density, but not bone macro-architecture at metaphyseal regions of weight-bearing bones, which is consistent with findings reported in children at the distal radius. These findings suggest that lower trabecular density at metaphyseal regions of long bones track throughout the appendicular skeleton and may be an early marker of skeletal fragility.Obese children are overrepresented in childhood fracture cases. Nevertheless, the effects of fat on bone during growth remain unclear. This study showed that skeletal muscle was a stronger determinant of bone parameters in girls than total body adiposity, although fat mass had a persistent, albeit weak association with bone parameters. Furthermore, fatty infiltration of skeletal muscle, which is associated with type 2 diabetes mellitus, was inversely associated with bone strength in girls. These findings are consistent with the proposed functional model of bone development which posits that forces from muscle contractions are the main mechanical challenges to which bones adapt.Physical activity during growth is critical for optimal bone development. The findings from this study support this premise and suggest that regular physical activity enhances bone strength in girls. Nevertheless, for exercise to be accepted as an important public health osteoporosis prevention strategy, lasting adaptations must be shown. Plausible biological explanations have been offered in support of the peri-pubertal years as a "window of opportunity" for maximizing the response to exercise. Findings from this study suggest that a two year school-based high-impact jumping intervention was not an effective means to enhance bone parameters in girls. Controlled dose-response trials will be necessary to test questions regarding the types, bouts, and durations of exercise required to define the "dose" of exercise needed to elicit meaningful skeletal adaptations during growth.

Over the past several decades abdominal obesity and physical inactivity have increased at an alarming pace. Since both are related to adverse health risk it is important to determine their independent influence. It is well established that cardiorespiratory fitness (CRF, the ability to perform physical activity) and physical activity (PA) are negatively associated with cardiometabolic risk factors (commonly obtained risk factors for disease, e.g: TG, HDL, etc.). In other words, the higher a person’s levels of PA and fitness, the lower that person’s likelihood of developing cardiometabolic risk factors. Abdominal obesity is positively associated with cardiometabolic risk factors which means the more abdominally obese a person is, the more prone that person is to develop cardiometabolic risk factors. However, it is unknown whether PA influences cardiometabolic risk factors independent of fitness level and/or abdominal obesity. My study objective was to examine whether PA is associated with cardiometabolic risk factors independent of cardiorespiratory fitness and/or abdominal obesity in inactive abdominally obese women. The study enrolled 141 inactive abdominally obese women. PA, cardiorespiratory fitness, and cardiometabolic risk profile were measured in all participants. A novel feature of this study was the use of the accelerometer to objectively measure PA and to divide exercise into different levels of intensity, such as: low PA, moderate to vigorous PA (MVPA), etc. My findings revealed that abdominal obesity was positively associated with cardiometabolic risk independent of PA or CRF. I also observed that CRF was inversely related to cardiometabolic risk independent of PA or abdominal obesity. MVPA explained cardiometabolic risk factors by itself, but with insulin resistance measurements (2-hour glucose, and homeostasis model of assessment) this relationship was abolished when abdominal obesity and CRF were also taken into consideration. The findings of this study provide further support for the recommendation that waist circumference and CRF be included as routine measures screening for cardiometabolic risk factors in inactive obese women. Our findings also support the suggestion that even modest amounts of daily MVPA that are below the recommended threshold of 30 minutes/day convey health benefit. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2013-07-23 13:46:57.088

In consideration of the rising prevalence of obesity and its effect on metabolic health and disease, this study was conducted to examine mechanisms involved in adipose tissue function following an acute bout of exercise in abdominal subcutaneous adipose tissue. Sedentary, overweight/obese women (n=10, BMI=30.6±6.0 kg∙m-2, VO2peak=30.3±5.4 mL•kg-1•min-1) completed 2 visits to the lab in which they either exercised for 1 hour or a rested in bed for the equivalent time (control). Experiments were executed randomly using a randomized cross-over study design. Gas exchange measures were measured at three time points before biopsies and subcutaneous adipose biopsies were obtained pre-condition, immediately after condition (0hr), two hours post (2hr), and four hours post (4hr). Acute exercise had significant effects whole body fat oxidation and phosphorylation of insulin signalling proteins, but had no effect on the phosphorylation of proteins regulating the expression of glyceroneogenic genes. In combination, these results suggest that acute exercise can transiently decrease insulin signalling although the mechanism by which this occurs is unclear. Additionally, acute exercise had no effect on the phosphorylation of proteins that are thought to regulate glyceroneogenic gene expression, suggesting that there are either alternative mechanisms involved or that time since the consumption of a meal is a greater stimulus for the activation/upregulation of glyceroneogenesis. Our findings suggest that acute exercise may acutely alter function of adipose tissue such that it contributes to elevations in whole body fatty acid metabolism, however, whether or not chronic adaptations are induced remains an important area for future study. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2013-09-25 20:39:11.506

Introduction: An increased gluteofemoral adipose tissue (AT) mass is associated with a protective cardiovascular and metabolic risk profile, and effective fatty acid retention in femoral AT has been proposed as a possible mechanism. Catecholamines are important regulators of AT lipolysis and blood flow (ATBF). The aim of the thesis was to investigate regional differences in the adrenergic regulation of fatty acid release and ATBF between abdominal and femoral AT in vivo. Furthermore, in vivo regional fatty acid trafficking was studied in a physiological setting over 24 h. Methods: Regional fatty acid trafficking, along with the measurement of ATBF, was studied with the arterio-venous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline) were infused either locally by microinfusion, or systemically. Local microinfusion of adrenoreceptor antagonists (propranolol, phentolamine) was used to characterize specific adrenoreceptor subtype effects. The trafficking of dietary fatty acids was studied over a 24 h period involving three meals containing stable isotope-labelled fatty acids along with intravenous infusions of another labelled fatty acid. Results: Femoral ATBF and lipolysis was less responsive to adrenergic stimulation with adrenaline compared to abdominal AT. This was due to increased femoral α-adrenoreceptor responsiveness. When studied over 24 h, femoral AT showed a lower lipolysis rate compared to abdominal AT, while dietary fatty acids were extracted more avidly by abdominal AT. Uptake of non-dietary fatty acids (derived from very-low-density lipoproteins or unbound non-esterified fatty acids) was comparable between abdominal and femoral AT. Conclusion: There are fundamental differences in response to adrenergic stimuli between abdominal and gluteofemoral tissues and the ability of femoral AT to trap non-dietary fatty acids may provide protection of other tissues from ectopic fatty acid deposition.

Recently, a genome-wide analysis identified DNA methylation of the HIF3A (hypoxia-inducible factor 3A) as strongest correlate of BMI. Here we tested the hypothesis that HIF3A mRNA expression and CpG-sites methylation in adipose tissue (AT) and genetic variants in HIF3A are related to parameters of AT distribution and function. In paired samples of subcutaneous AT (SAT) and visceral AT (VAT) from 603 individuals, we measured HIF3A mRNA expression and analyzed its correlation with obesity and related traits. In subgroups of individuals, we investigated the effects on HIF3A genetic variants on its AT expression (N = 603) and methylation of CpG-sites (N = 87). HIF3A expression was significantly higher in SAT compared to VAT and correlated with obesity and parameters of AT dysfunction (including CRP and leucocytes count). HIF3A methylation at cg22891070 was significantly higher in VAT compared to SAT and correlated with BMI, abdominal SAT and VAT area. Rs8102595 showed a nominal significant association with AT HIF3A methylation levels as well as with obesity and fat distribution. HIF3A expression and methylation in AT are fat depot specific, related to obesity and AT dysfunction. Our data support the hypothesis that HIF pathways may play an important role in the development of AT dysfunction in obesity.

The increasing prevalence of obesity and related health complications, such as type 2 diabetes, cardiovascular disease and cancer, demands thorough investigation of the underlying processes. One of the key tissues investigated in this context is adipose tissue. It is becoming increasingly clear that adipose tissue is a very dynamic and heterogenic organ. This thesis provides an overview of various aspects of adipose biology that illustrate its heterogenic nature and describes my own scientific contributions to this field. We typically distinguish between thermogenic, energy-expending brown adipocytes and energy-storing white adipocytes that are located in anatomically distinct adipose depots. In addition, brite (or beige) adipocytes are functionally thermogenic, but are located among white adipocytes. Related to functional variation, adipocytes and adipose tissues display a wide range of morphological appearances. An additional property that illustrates the heterogeneity among adipose cells and depots is the variation of cellular responses to physiological cues, such as changes in diet or environmental temperature. Furthermore, the developmental origins of various adipose types display great heterogeneity, which may explain some of the functional and dynamic differences that are observed. In line with the complexity of developmental origins, molecular markers that were initially proposed to distinguish between brown, brite/beige and white adipose subtypes have added to the notion that the composition of the adipose organ is much more complex than has long been appreciated. My own work has contributed to the enhancement of our understanding of the heterogeneity of adipose subtypes. In particular, my findings related to marker gene expression patterns have led to increased appreciation of the complex nature of adipose gene expression patterns and the complications of translating results obtained in mice to humans. Some of my other contributions have increased the understanding of the differences and similarities in thermogenic adipose tissue functionality and dynamics. With cell culture studies, I have revealed new characteristics of pre-adipose cells from various depots that further add to the appreciation of the adipose heterogeneity. Overall, this thesis provides an overview of important characteristics of the adipose organ, illustrating its heterogenic nature. Realization of this heterogeneity is of importance in order to properly study the adipose organ to ultimately understand how the adipose organ can be therapeutically targeted to effectively treat adipose-related diseases. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 7: Manuscript. Paper 8: Manuscript.</p>

O uso crônico de altas doses de glicocorticoides (GC) aumenta tecidos adiposos (TA) centrais. Essa pesquisa visou verificar os efeitos do uso contínuo de GC em doses mais baixas sobre diferentes TAs. Ratos Wistar machos com 10 semanas de vida foram divididos em 2 grupos: controle (CON) e cortisol (CORT) e foram implantados com minibomba osmótica, pela qual o grupo CORT recebeu 0,6 mg/kg/d de cortisol e o grupo CON recebeu salina, por 6 semanas. Os resultados mostram um aumento da gordura subcutânea (SC) abdominal dos animais CORT, acompanhada de: aumento da atividade máxima das enzimas ATP-citrato-liase e glicose-6-fosfato desidrogenase; redução da expressão da enzima AMPK; aumento da expressão da enzima 11&#946;HSD1 e das triglicérides circulantes. Esses dados sugerem que a intervenção aumentou a SC abdominal devido maior atividade de enzimas lipogênicas e de um possível aumento da captação de lipídeos séricos por esse tecido, o que pode ter resultado do aumento da concentração local de GC provocado pela expressão aumentada da 11&#946;HSD1. / Chronic use of high doses of glucocorticoids (GC) increases central adipose tissue (AT). This research aimed to verify the effects of continuous use of lower doses of GC on different TAs. Male Wistar rats, 10 weeks old, were divided into 2 groups: control (CON) and Cortisol (CORT), and were implanted with osmotic minipump, whereby CORT group received 0.6 mg/kg/d of cortisol and CON group received saline, for 6 weeks. The results show an increase in abdominal subcutaneous fat (SC) of CORT animals accompanied by: increased maximum activity of ATP citrate lyase and glucose 6-phosphate dehydrogenase enzymes; reduced expression of AMPK enzyme; increased expression of 11&#946;HSD1 enzyme and circulating triglycerides. These data suggest that the intervention increased abdominal SC due to increased activity of lipogenic enzymes and a possible increase in the uptake of serum lipids through this tissue, which may have resulted from increased local GC concentration caused by increased expression of 11&#946;HSD1.

by Poon Mei Yu. / Thesis submitted in: Dec. 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 127-132). / Abstract also in Chinese. / Declaration --- p.i / Acknowledgement --- p.ii / Table of Contents --- p.iii / Abbreviations --- p.xi / List of Figures --- p.xiv / List of Tables --- p.xvii / Abstract --- p.xxi / Introduction --- p.1 / Chapter Chapter 1: --- Obesity & related abnormalities --- p.2 / Chapter Chapter 2: --- Measurement of body fat --- p.11 / Objective --- p.18 / Chapter Chapter 3: --- Purpose of study --- p.19 / Method --- p.24 / Chapter Chapter 4: --- Technical considerations on CT technique --- p.25 / Chapter Chapter 5: --- Data Collection --- p.32 / Chapter Chapter 6: --- Data Analysis --- p.44 / Results --- p.49 / Chapter Chapter 7: --- Amount of adipose tissue --- p.50 / Chapter Chapter 8: --- "Adipose tissue distribution, VSR & VTR" --- p.81 / Discussion --- p.105 / Chapter Chapter 9: --- Discussion --- p.106 / Conclusions --- p.122 / Chapter Chapter 10: --- Conclusions --- p.123 / References --- p.127 / Appendix I --- p.133 / Appendix II --- p.136 / Appendix III --- p.139 / DECLARATION --- p.i / ACKNOWLEDGEMENT --- p.ii / TABLE OF CONTENTS --- p.iii / Brief Contents --- p.iii / Detailed Contents --- p.v / ABBREVIATIONS --- p.xi / LIST OF FIGURES --- p.xiv / LIST OF TABLES --- p.xvii / ABSTRACT --- p.xxi / INTRODUCTION --- p.1 / Chapter Chapter 1: --- OBESITY & RELATED ABNORMALITIES --- p.2 / Chapter 1.1 --- Adipose Tissue --- p.2 / Chapter 1.2 --- Classification of Adiposity --- p.3 / Chapter 1.3 --- Obesity --- p.5 / Chapter Chapter 2: --- MEASUREMENT OF BODY FAT --- p.11 / Chapter 2.1 --- Methods of Measuring Body Fat --- p.11 / Chapter 2.1.1 --- Non-imaging Methods --- p.12 / Chapter 2.1.2 --- Imaging Methods --- p.13 / Chapter 2.1.2.1 --- Plain radiograph --- p.13 / Chapter 2.1.2.2 --- Ultrasound --- p.13 / Chapter 2.1.2.3 --- Computed tomography --- p.14 / Chapter 2.1.2.4 --- Magnetic resonance imaging --- p.16 / OBJECTIVE --- p.18 / Chapter Chapter 3: --- PURPOSE OF STUDY --- p.19 / Chapter 3.1 --- Objectives --- p.19 / Chapter 3.2 --- Explanation --- p.20 / Chapter 3.2.1 --- Best level of AT area measurement --- p.21 / Chapter 3.2.2 --- Linear AT dimension --- p.22 / Chapter 3.2.3 --- Sex and age differences --- p.22 / Chapter 3.2.4 --- Difference in attenuation interval of fat --- p.23 / METHOD --- p.24 / Chapter Chapter 4: --- TECHNICAL CONSIDERATIONS ON CT TECHNIQUE --- p.25 / Chapter 4.1 --- Defining Anatomy --- p.25 / Chapter 4.1.1 --- Abdominal visceral cavity --- p.26 / Chapter 4.1.1.1 --- Diaphragm --- p.26 / Chapter 4.1.1.2 --- Pelvis --- p.26 / Chapter 4.1.1.3 --- Boundary at mid-potion --- p.27 / Chapter 4.1.2 --- Intra- and retro- peritoneal compartments --- p.28 / Chapter 4.2 --- Attenuation interval of fat --- p.29 / Chapter 4.2.1 --- Distinctive pixel value vs. attenuation interval --- p.30 / Chapter 4.2.2 --- Choice of interval --- p.30 / Chapter Chapter 5: --- DATA COLLECTION --- p.32 / Chapter 5.1 --- Subjects --- p.32 / Chapter 5.2 --- Acquisition --- p.33 / Chapter 5.3 --- Measurement --- p.34 / Chapter 5.3.1 --- AT area measurement --- p.35 / Chapter 5.3.2 --- Linear AT measurement --- p.38 / Chapter 5.3.2.1 --- Subcutaneous AT thickness --- p.38 / Chapter 5.3.2.2 --- Visceral AT thickness --- p.39 / Chapter Chapter 6: --- DATA ANALYSIS --- p.44 / Chapter 6.1 --- Tools --- p.44 / Chapter 6.2 --- Mathematical Assumptions --- p.45 / RESULTS --- p.49 / Chapter Chapter 7: --- AMOUNT OF ADIPOSE TISSUE --- p.50 / Chapter 7.1 --- AT Volumes --- p.50 / Chapter 7.1.1 --- In male and female subgroups --- p.50 / Chapter 7.1.2 --- VAT and SAT increase with TAT --- p.52 / Chapter 7.1.3 --- A VAT volume vs. VAT volume --- p.54 / Chapter 7.2 --- AT Areas at Various Anatomical Levels --- p.55 / Chapter 7.2.1 --- In male and female subgroups --- p.56 / Chapter 7.2.2 --- Correlation between AT volumes and areas --- p.62 / Chapter 7.2.3 --- Prediction of abdominal AT volumes from AT areas --- p.63 / Chapter 7.3 --- Linear AT Dimensions --- p.66 / Chapter 7.3.1 --- Linear SAT dimensions correlated to AT volumes --- p.66 / Chapter 7.3.2 --- Linear VAT dimensions correlated to AT volumes --- p.68 / Chapter 7.3.3 --- Prediction of abdominal SAT volume --- p.70 / Chapter 7.3.4 --- Prediction of abdominal A VAT volume --- p.71 / Chapter 7.3.5 --- Prediction of abdominal TAT volume --- p.72 / Chapter 7.4 --- "AT Measurements, Sex and Age" --- p.73 / Chapter 7.4.1 --- In whole study population --- p.73 / Chapter 7.4.2 --- In male and female subgroups --- p.75 / Chapter 7.5 --- Difference in Attenuation Interval --- p.79 / Chapter Chapter 8: --- DISTRIBUTION OF ADIPOSE TISSUE: VSR & VTR --- p.81 / Chapter 8.1 --- VSR --- p.81 / Chapter 8.1.1 --- Correlation --- p.82 / Chapter 8.1.2 --- Prediction --- p.83 / Chapter 8.1.3 --- Effect of attenuation interval --- p.84 / Chapter 8.1.3.1 --- On VSR value --- p.84 / Chapter 8.1.3.2 --- On correlation and prediction results --- p.86 / Chapter 8.2 --- VTR --- p.88 / Chapter 8.2.1 --- Correlation --- p.88 / Chapter 8.2.2 --- Prediction --- p.89 / Chapter 8.2.3 --- Effect of attenuation interval --- p.91 / Chapter 8.2.3.1 --- On VTR value --- p.91 / Chapter 8.2.3.2 --- On correlation and prediction results --- p.93 / Chapter 8.3 --- VSR vs. VTR --- p.95 / Chapter 8.4 --- "VSR, VTR, Sex and Age" --- p.96 / Chapter 8.4.1 --- Correlation --- p.99 / Chapter 8.4.2 --- Prediction --- p.100 / Chapter 8.4.3 --- VSR and VTR increase with age --- p.101 / DISCUSSION --- p.105 / Chapter Chapter 9: --- DISCUSSION --- p.106 / Chapter 9.1 --- Absolute AT Content (Amount) --- p.106 / Chapter 9.1.1 --- AT areas of various anatomical levels --- p.106 / Chapter 9.1.1.1 --- Correlated to AT volume --- p.107 / Chapter 9.1.1.2 --- Prediction of abdominal A T volume: best level --- p.107 / Chapter 9.1.2 --- Linear AT dimensions --- p.109 / Chapter 9.1.2.1 --- Correlated to AT volume --- p.109 / Chapter 9.1.2.2 --- Prediction of abdominal AT volume --- p.111 / Chapter 9.2 --- AT Distribution Indices: VSR and VTR --- p.112 / Chapter 9.2.1 --- The best level --- p.114 / Chapter 9.3 --- Sex and Age Difference --- p.114 / Chapter 9.3.1 --- absolute AT content --- p.114 / Chapter 9.3.2 --- VSR and VTR --- p.116 / Chapter 9.4 --- Difference in Attenuation Interval --- p.118 / Chapter 9.4.1 --- Absolute AT content --- p.118 / Chapter 9.4.2 --- VSR and VTR --- p.119 / Chapter 9.5 --- Limitations --- p.120 / Chapter 9.5.1 --- Study population --- p.120 / Chapter 9.5.2 --- Differentiation of compartments --- p.121 / CONCLUSIONS --- p.122 / Chapter Chapter 10: --- CONCLUSIONS --- p.123 / Chapter 10.1 --- Absolute AT Content in Abdomen --- p.123 / Chapter 10.2 --- Abdominal AT Distribution --- p.125 / Chapter 10.3 --- Effect of Attenuation Interval --- p.126 / REFERENCES --- p.127 / APPENDIX I: Comparison of study populations & scanning techniques --- p.133 / APPENDIX II: Comparison of definitions of attenuation interval of fat and anatomical compartments --- p.136 / APPENDIX III: Statistical summary of the adipose tissue measurements in this study --- p.139

Long-term excessive positive energy balance results in overweight and obesity, which is caused by adipose tissue deposition. This increases the occurrence of cardiovascular diseases and type 2 diabetes. Adipose tissue plays an active role in the development of these diseases and so it is important to understand how this tissue responds to relevant stimuli such as feeding, fasting and physical activity. The study in Chapter 4 examined the impact of fasting and feeding, on adipose tissue responsiveness to prolonged moderate intensity exercise. Ten healthy overweight men aged 26 ± 5 years (mean ± SD) with a waist circumference of 105 ± 10 cm walked at 60% of maximum oxygen uptake under either fasted (12 h overnight fasting) or fed (70% carbohydrate breakfast) conditions in a randomised, counterbalanced design. Feeding comprised 648 ± 115 kcal 2 h before exercise. The expression of several metabolism-related adipose tissue genes was acutely regulated whilst participants undertook fasted exercise, including up-regulation of lipolytic lipase and transporter (adipose triglyceride lipase, hormone sensitive lipase & fatty acid translocase/CD36), glycolytic inhibitor (pyruvate dehydrogenase 4), insulin singling molecules (glucose transporter type 4 & insulin receptor substrate 2) as well as adipose insulin receptor substrate 2 protein contents (all p ≤ 0.05), compared to exercise in the fed state. The results indicate that adipose tissue responsiveness to prolonged exercise is affected by the dietary conditions. The study in Chapter 5 examined whether adipose tissue would be influenced by more modest changes in accumulated physical activity. Eleven overweight participants (7 men and 4 post-menopausal women) aged 50 ± 5 years (means ± SD) completed two identical mixed meal (~1,700 ± 360 kcal in total) feeding trials (prolonged sitting versus breaking sitting) in a randomised, counterbalanced design. The breaking sitting intervention comprised walking for 2 min every 20 min over 5 h. The results demonstrated that postprandial insulin and glucose concentrations were attenuated (all p ≤ 0.05) while participating in regular small bouts of walking but this did not affect adipose tissue metabolic- and insulin-associated pathways in adipose tissue. The study in Chapter 6 examined the responsiveness to aforementioned different forms of physical activity (a single bout of prolonged exercise versus accumulation of small bout of physical activity) on a challenge imposed by 50% overfeeding. Twenty-four lean, active and healthy men aged 21 ± 3 years were recruited. Participants were randomised to either an overfeeding with restricted physical activity (≤ 4,000 steps per day) group (OVER, n = 8), overfeeding with restricted physical activity (≤ 4,000 steps per day) plus daily 45 min endurance moderate intensity walking group (50% V̇O2max) (OVER + EN, n = 8) or overfeeding with restricted physical activity (≤ 4,000 steps per day) plus intermittent breaking sitting group (OVER + BREAKS, n = 8). All groups achieved the same overfeeding (50% of overfeeding based on their habitual diet). Notably, despite the impairment of insulin sensitivity as a result of the energy surplus, the accumulation of small bouts of physical activity blunted overfeeding induced up-regulation of adipose lipogenetic activity (i.e. the down-regulation of sterol regulatory element binding protein 1c and fatty acid synthase) and circulating inflammation (i.e. no change of white blood cell count) compared to energy surplus with sedentary lifestyle and/or overfeeding plus a single bout of moderate intensity exercise. This could mean that the form of physical activity undertaken could play a key role in lipogenesis activation. Based on the results from this thesis, it appears that energy consumption and physical activity are both capable of acutely and chronically influencing adipose tissue metabolic signalling and regulation.

The overall aim of the work presented in this thesis was to further characterise aspects of metabolic and immune system cross-talk in human subcutaneous adipose tissue, with a particular emphasis on the potential role of T-lymphocytes in adipose tissue dysfunction and insulin resistance. Chapter 3 characterised macrophage and T-lymphocyte populations residing in adipose tissue from lean through to class I obese men. This work demonstrated that T-lymphocytes display increased activation with increased adiposity and that potential compensatory mechanisms may be present to help counteract adipose tissue inflammation. In Chapter 4, the same participants were exposed to a meal-based stimulus in order to examine the postprandial metabolic and inflammatory responses in blood and adipose tissue. Despite increased glucose and insulin responses in blood with obesity, there were no differences in inflammatory cytokine gene expression responses in adipose tissue. This suggests that mechanisms may be present to limit or dampen inflammatory output from adipose tissue after feeding in individuals with modestly increased adiposity. Chapter 5 examined metabolic and immune system changes to 50 % calorie restriction for 3 days, resulting in reduced serum leptin which was temporally associated with a reduction in blood T-lymphocyte activation. In adipose tissue, however, leptin gene expression/secretion was not reduced and neither was resident T-lymphocyte activation, indicating that there may be local tissue-specific responses of immune cells to caloric restriction. Chapter 6 characterised differences between obese individuals with either normal or impaired glucose tolerance, and their respective responses to 10 days of diet and activity modification. Overall, this thesis highlights key differences in properties of T-lymphocyte populations with increasing levels of adiposity and insulin resistance together with responses in adipose tissue and the immune system in times of feeding, severe calorie restriction and glucose lowering diet and activity.