The incidence of obesity, type 2 diabetes and cardiovascular disease (CVD) is increasing at alarming rates worldwide. Obesity is associated with a chronic nutrient surplus that contributes to chronic low-grade inflammation, ectopic lipid deposition and insulin resistance. Insulin resistance is an important factor contributing to the development of both type 2 diabetes and CVD. Therefore, therapies that can address multiple aspects of cardio-metabolic diseases could have significant clinical utility to reduce morbidity and mortality associated with these conditions. Several distinct glucose lowering therapies have been developed, targeting unique molecular targets. Interestingly, three district glucose lowering therapies, metformin, canagliflozin and salsalate have been shown to potently activate the central energy regulating enzyme, AMP activated protein kinase (AMPK). Activation of AMPK has been shown to be important for regulating fatty acid and cholesterol synthesis, fatty acid oxidation, glucose homeostasis, inflammation and whole-body energy expenditure. Therefore, the objective of this thesis was to examine the effects of metformin, canagliflozin and salsalate, on obesity, atherosclerosis, hepatic lipid metabolism, and macrophage inflammatory signalling and to delineate the mechanism(s) by which these changes occur. In this thesis we show that metformin reduces obesity through a circulating hormone GDF15, and that AMPK is not required for metformin induced GDF15 secretion. Additionally, we show that canagliflozin reduces hepatic cholesterol synthesis and macrophage IL1-1β secretion through mechanisms requiring AMPKβ1. Lastly, we show that salsalate reduces atherosclerosis in a manner dependent on macrophage AMPK β1 and this is associated with reduced macrophage proliferation in vitro and in vivo. These insights into the mechanisms by which these glucose lowering therapies elicit beneficial effects on obesity and atherosclerosis further our understanding of the potential use of these agents for treatments beyond improved glycemic control. Furthermore, this evidence can direct future drug development or drug combinations to more effectively treat multiple aspects of these common chronic diseases that affect over a billion people worldwide. / Thesis / Doctor of Philosophy (Medical Science)

Melanocortins play a key role in appetite regulation across species. One such melanocortin, beta-melanocyte stimulating hormone (beta-MSH) is receiving increasing attention for its anorexigenic effects. In chicks selected for low (LWS) and high (HWS) juvenile body weight, beta-MSH differentially decreased food intake and HWS chicks may be more sensitive to its effects. Both lines responded similarly to beta-MSH with decreased water intake. While whole blood glucose concentrations and ingestive and non-ingestive behaviors (sit, stand, preen, perch, deep rest, jumps, escape attempts, feed pecks, defecations, and total distance traveled) were not affected in either line, beta-MSH increased corticosterone in LWS chicks but not HWS chicks. However, despite the increase in corticosterone concentration in LWS, astressin, a corticotrophin releasing hormone (CRH) receptor antagonist, did not attenuate the effects of beta-MSH in either line suggesting that the altered stress response may not be acting via CRH receptors. When beta-MSH was co-administered with HS014, a highly selective antagonist for the melanocortin 4 receptor, only LWS responded with an attenuated response to beta-MSH suggesting that the differential response may in part be due to altered receptor affinity or binding resulting from the selection process. To investigate the roles of the hypothalamus and hindbrain in the differential food intake response, an experiment was designed where chicks were injected targeting either the lateral or 4th ventricle utilizing a novel freehand injection procedure. Chicks from both lines responded similarly to beta-MSH following both lateral and 4th ventricle injections. Together, these data suggest that alterations in the b-melanocortinergic appetite regulation system may be in part responsible for the differential body weights of the LWS and HWS lines. [Adaptations of chapters II, III, and IV have been published in Neuroscience Letters, Journal of Neuroendocrinology, and Behavioural Brain Research, respectively] / Ph. D.

Nearly 50% of the equine population is overweight due to feeding and management practices. Obesity is related to development of diseases that are detrimental to performance and potentially fatal in horses, including insulin resistance, laminitis, and equine metabolic syndrome (EMS). Objectives of this research included first, characterization of nutrition-related management practices of hunter/jumper show industry via a voluntary survey; second, evaluating the Body Condition Index (BCI) in comparison to the Body Condition Scoring system (BCS) in sporthorses; and lastly, determining the effects of a hindgut buffer in overconditioned horses following an abruptly introduced moderate nonstructural carbohydrate (NSC) meal. There were no differences in nutritional management between hunter and jumper disciplines and most representatives (n=89) had no nutritional concerns. Many used trainers (38%) and veterinarians (36%) as sources of nutritional advice rather than professional equine nutritionists (7%). BCI had consistently higher scores than BCS (P<0.01), with the largest differences in horses with BCS < 5. Horses were offered a concentrate meal containing 1.2g NSC/kg BW with and without DigestaWell® Buffer (DB). Horses receiving DB had decreased plasma L-lactate (P=0.05), and a tendency for increased fecal pH (P=0.08) and decreased fecal D-lactate (P=0.07). These studies demonstrate a need to improve horse owner education and the relationship between representatives and trained nutritionists to reduce disease incidence, that different equations may need to be developed for a more consistently accurate BCI across various breed and body types, and that DB may have a positive impact on the equine digestive response to NSC. / Master of Science

Obesity is associated with an increased risk of falls and subsequent injury. Previous studies have shown weight loss and strength training to be beneficial to balance, but knowing which is more beneficial will allow researchers to design interventions to maximize the benefits in terms of balance and reducing risk of falls. Therefore, the purpose of the first study was to evaluate the effects of weight loss and strength training on balance recovery using a combination of laboratory experiments and mathematical modeling. Nine male subjects with BMI 30.1 to 36.9 kg/m² were released from a forward lean and attempted to recover balance using an ankle strategy. Lean angle was increased until subjects required a step or hip flexion to recover balance. The maximum lean angle, θ_max, was used as the measure of balance recovery capability. Experimental data were used as inputs to an inverted pendulum model of balance recovery. Multiple simulations were used to determine the effects of strength (maximum ankle torque and ankle torque generation rate) and weight loss on θ_max. Changes in weight and strength were linearly related to changes in θ_max. A 6.6 ± 0.4% decrease in weight or 6.9 ± 0.9% increase in strength were estimated as required to improve (increase) θ_max by 1 degree. Based on these results, balance recovery using an ankle strategy can improve with either reductions in weight or increases in strength. In addition, weight loss may be a more effective intervention than strength gain at improving balance recovery capability. The purpose of the second study was to quantify changes in body segment inertial parameters (BSIPs) with weight loss. These data were needed to alter BSIPs in the first study to mimic changes with weight loss. Both before and after weight loss, magnetic resonance imaging scans were acquired along the length of the body and were used to calculate segment masses, COM positions, and radii of gyration. A number of significant changes in BSIPs occurred with weight loss. / Master of Science

Yes / There is an absence of evidence about interventions to prevent or treat obesity in early childhood and in South Asian populations, in whom risk is higher. Objectives: To study patterns and the aetiology of childhood obesity in a multiethnic population and develop a prevention intervention. Design: A cohort of pregnant women and their infants was recruited. Measures to compare growth and identify targets for obesity prevention, sensitive to ethnic differences, were collected. A feasibility randomised controlled trial (RCT) was undertaken. Setting: Bradford, UK. Participants: A total of 1735 mothers, 933 of whom were of South Asian origin. Intervention: A feasibility trial of a group-based intervention aimed at overweight women, delivered ante- and postnatally, targeting key modifiable lifestyle behaviours to reduce infant obesity. Main outcome measures: The feasibility and acceptability of the pilot intervention. Data sources: Routine NHS data and additional bespoke research data. Review methods: A systematic review of diet and physical activity interventions to prevent or treat obesity in South Asian children and adults. / National Institute for Health Research

Yes

This Thesis attempts to question how the built environment affects public and planet health. I am particularly concerned with childhood obesity and how it is related to the affordability of neighborhoods, accessibility to public parks, availability of healthy food, and accountability for sustainability within our cities and suburbs. The architectural design proposal is an Elementary School, in Old Town Alexandria, that promotes learning through activity and play, is a living laboratory for environmental stewardship, and fosters a strong sense of community. / Master of Architecture

The prevalence of overweight and obesity in the feline population is estimated to be 25.7% and 33.8%, respectively. Feline obesity is associated with comorbidities such as insulin resistance and hepatic lipidosis. Several risk factors are associated with obesity including middle age, neuter status, decreased activity, and diet. Obesity management is multifaceted and includes client education, diet modification, and consistent monitoring. Successful obesity management may be dependent on owner perception of their cat's quality of life during a prescribed weight loss plan. Poor quality of life perception may result in failure to complete the weight loss process. Food toys may be used to enhance environmental enrichment, allow cats to express their natural predatory behavior and overall improve owner-perceived quality of life. Therefore, we set out to investigate the role of food toys in owner-perceived quality of life of obese cats during a prescribed weight loss plan. Fifty-five cats with a BCS > 7 were enrolled in a double-blinded weight loss study and randomized into one of two groups: food toy (n=26) or food bowl (n=29). Each cat was provided a prescribed weight loss diet and instructions. Body weight and body condition score were evaluated monthly. Additionally, owners completed a monthly questionnaire to assess their cat's quality of life. Of the 44 cats in the final analysis, 66% (n=29) successfully completed the study and lost > 2 BCS points and/or achieved an ideal BCS of 5/9. Low-calorie vegetables were offered to the majority of cats (n= 32) due to owner reports of disruptive food seeking behavior. Of the cats offered vegetables, 87.5% (n=28) cats required a commercial palatant to consume the vegetables. All enrolled cats had a higher (p<0.0000) owner-perceive quality of life at the final visit/recheck/end of study (median QOL=110.0), as compared to the initial weight loss appointment (median QOL=126.0). The increase in quality of life was primarily driven by improvement in moving from one place to another, grooming and scratching, engaging in social activities, and playing and hunting. There was no effect (p=0.27) of food toy on owner-perceived quality of life. Prescribed weight loss improves owner-perceived quality of life of obese cats. A single food toy (ball-style) was included in this study and did not appear to influence owner-perceived QOL. However, the role of food toys needs further investigation as there are several food toy styles that have not yet been investigated during a prescribed weight loss plan. We suspect that most/all of the 32 cats fed vegetables would have withdrawn from the study. Therefore, including vegetables in the prescribed weight loss plan appears to improve success of weight loss in obese cats. / Master of Science / About 60% of cats are overweight or obese, which equates to about 56 million cats in the United States. Feline obesity is associated with poor health outcomes such as insulin resistance and fatty liver disease. Risk factors for feline obesity include middle age, neutered, decreased activity, and diet. Obesity is commonly diagnosed via body condition scoring in small companion animals. Owner-perceived quality of life is an important factor for a successful weight loss plan. Low perceived quality of life may result in owners abandoning the weight loss process. Food toys provide environmental enrichment, slow food consumption and may increase activity. However, the impact of food toys on owner-perceived quality of life and the success of a weight loss plan were not previously investigated. Fifty-five cats were enrolled into the weight loss study and randomly placed into one of two groups. Twenty-six cats were placed in the food toy group, and 29 cats were placed in the food bowl group. Monthly follow-up visits consisted of weighing and body condition scoring each cat. In addition, owners completed a questionnaire to evaluate their cat’s quality of life. Food toys did not influence cat owner perception of their cat’s quality of life. However, cat owners perceived their cat’s quality of life to be higher at the end of the study compared to the beginning for all cats. The increase in quality of life was primarily driven by improvement in moving from one place to another, grooming and scratching, engaging in social activities, and playing and hunting. Satiety was an issue for several cats during the study. Low-calorie vegetables were offered to over half of the study cats to decrease hunger and food-seeking behavior. This study indicates quality of life is increased in cats undergoing a prescribed weight loss plan. A single food toy was utilized in the present study although several types of food toys are currently available that have not been investigated in relation to owner-perceived quality of life during a prescribed weight loss plan.

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Yeung, Daniel Chi Shing. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 69-83). / Abstracts in English and Chinese; appendix B also in Chinese. / ACKNOWLEDGMENTS --- p.i / ABSTRACT --- p.ii / TABLE OF CONTENTS --- p.vi / INTRODUCTION --- p.1 / Purpose and Significance --- p.3 / Hypothesis --- p.5 / Delimitation --- p.5 / Limitation --- p.5 / Operational Definitions --- p.6 / REVIEW OF LITERATURE --- p.9 / The Epidemic of Childhood Obesity --- p.9 / Increase in Childhood Obesity Over the World --- p.9 / Factors Contribute to Childhood Obesity --- p.12 / Health Consequence --- p.14 / Childhood Obesity Interventions --- p.15 / Measurement of Body Composition in Children --- p.17 / Body Composition Models --- p.17 / Measurement Methods --- p.20 / Laboratory Methods --- p.20 / Hydrodensitometry --- p.20 / Air displacement plethysmography --- p.22 / Hydrometry --- p.23 / Dual energy X-ray absorptiometry --- p.25 / Pros and cons of body fat criterion measures --- p.26 / Field Methods --- p.27 / Bioelectric impedance analysis --- p.27 / Anthropometry --- p.28 / Skinfold thickness measurement --- p.29 / Summary --- p.33 / METHODOLOGY --- p.36 / Participants --- p.36 / Experimental Protocols and Procedures --- p.36 / Criterion Measurement --- p.36 / Field Measurements --- p.38 / Statistical A nalysis --- p.39 / RESULTS --- p.41 / Comparison of ADP and DXA in Measuring Percent Fat Criterion --- p.41 / Sample Distribution and Descriptive Statistics --- p.41 / Correlations --- p.44 / Reliability --- p.46 / Cross Validation of Slaughter Equations --- p.47 / Exploration of Alternative Equations --- p.51 / DISCUSSION --- p.59 / Limitations --- p.66 / Recommendations for Future Study --- p.67 / Conclusions --- p.68 / REFERENCES --- p.69 / APPENDIX / Chapter A --- Standardized Description of Skinfold Sites --- p.84 / Chapter B --- Informed Consent --- p.85 / Chapter C --- Data Sheet --- p.87