Introduction: The increased survival rates of children with brain tumors is the result of decades of advancement in diagnostic and therapeutic approaches, but brought the adverse long-term effects of the treatments and tumors on these children into focus. Survivors of childhood brain tumors (SCBT) are at an increased risk of cardiometabolic disorders and premature mortality. Obesity and excess adiposity are well-established risk factor for cardiometabolic risk in the general population, but its contribution to these outcomes in survivors is unknown. More recently, adiposity has emerged as a more robust predictor of cardiometabolic risk than body mass index, the most clinically used measure of obesity. The current thesis pursued four objectives: 1) to determine the prevalence of obesity and excess adiposity in SCBT 2) to explore adiposity and its determinants in SCBT 3) to investigate the determinants of obesity in SCBT and 4) to identify potentially effective interventions to manage obesity in SCBT. Methods: Systematic reviews and meta-analyses were used to evaluate the prevalence and interventions for overweight and obesity in SCBT while the determinants of adiposity and obesity were explored using primary data and regression analyses. General health information and brain tumors information were collected with standardized questionnaires and review of medical records. The overweight or obesity status of subjects was determined by body mass index (BMI), and adiposity profile was evaluated using percent body fat (%FM), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). Results: The results show no difference between the overweight and obesity rates in SCBT and non-cancer controls. However, SCBT have higher total and central adiposity. Birth weight is found to be a predictor of future BMI in SCBT, while a higher total adiposity in SCBT is predicted by having supratentorial tumors and receiving radiotherapy. Lastly, not enough evidence is available to conclude the effectiveness of lifestyle interventions, pharmacotherapy, and bariatric surgery on managing obesity in SCBT. Conclusions: Obesity, determined by BMI, is not enough to determine cardiometabolic risks in SCBT. Total and central adiposity should be measured as well to identify high-risk group. Special attention should be paid to SCBT with high birth weight, supratentorial tumors, and having received radiotherapy. Lastly, more randomized controlled trials are needed to provide high-quality evidence to determine the effectiveness of interventions to manage obesity and improve outcomes in SCBT. / Thesis / Master of Science (MSc) / Brain tumors are the most common solid tumors in children. The survival rates among children with brain tumors have increased significantly over the past four decades due to advances in early detection and treatment. However, these children are at increased risk of heart disease and type 2 diabetes, and early death. Evidence has suggested obesity and excess body fat as main reasons for cardiometabolic disorders in the general population, but it is not known if obesity and excess body fat contribute to diabetes and heart disease in survivors. Therefore, the current thesis aims to explore obesity and adiposity, their predictors and any existing treatments available to survivors of childhood brain tumors (SCBT) to see if outcomes can be improved. The results show that while survivors of childhood brain tumors have similar overweight and obesity rates to the general population when measured by the most common clinical measure, called body mass index (BMI), they in fact have higher fat mass. Furthermore, we identified birth weight as a predictor of obesity while the location of the tumors and receiving radiation therapy as predictors of the fat mass in SCBT. The results also show the lack of current effective interventions to manage obesity in SCBT. This data is critical to consider in the design and implementation of strategies to reduce heat disease and diabetes in survivors to improve their quality of life and lifespan.

An animal model to study complications resulting from childhood obesity is lacking. Our objective was to develop a porcine model for studying mechanisms underlying diet-induced childhood obesity. Pre-pubertal female pigs, age 35 d, were fed a high-energy diet (HED; n = 12), containing tallow and refined sugars, or a control corn-based diet (n = 11) for 16 wk. Initially, HED pigs self-regulated energy intake similar to controls, but, by wk 5, consumed more (P < 0.001) energy per kg body weight. At wk 15 and 22, pigs were subjected to an oral glucose tolerance test (OGTT); blood glucose increased (P < 0.05) in control pigs and returned to baseline levels within 60 min. HED pigs were hyperglycemic at time 0, and blood glucose did not return to baseline (P = 0.01), even 3 h post-challenge. During OGTT, glucose area under the curve was higher and insulin area under the curve was lower in HED pigs compared to controls (P = 0.001). Pigs given 6 wk of dietary intervention, consuming a control diet, marginally improved glucose area under the curve and LDL-cholesterol although insulin area under the curve was unaffected. Chronic HED intake increased (P < 0.05) subcutaneous, intramuscular, and perirenal fat deposition, and induced hyperglycemia, hypoinsulinemia, and low-density lipoprotein hypercholesterolemia; however, a 6 wk dietary intervention partially recovered a normal physiology. These data suggest pre-pubertal pigs fed HED are a viable animal model for studying childhood obesity. / Master of Science

Background: The prevalence of overweight, obesity and obesity-related disease, mainly cardiovascular disease (CVD), is increasing in both developed and developing countries. Ethnic differences have been reported in the prevalence of overweight, obesity and CVD. However, measures used to define overweight and obesity, and identify increased risk of CVD were developed and validated in predominately Caucasian populations in developed countries. Consequently, these measures may not accurately define disease risk in all population groups. Therefore the specific aims of this programme of study were: 1. To establish the relationship between adiposity and cardiovascular risk factors in different ethnic groups. 2. To identify field measures of adiposity, relating to cardiovascular risk in different ethnic groups. 3. To compare the relationship of adiposity and cardiovascular risk factors in a single ethnic group, that of a rural and an urban population in Zimbabwe. 4. To identify risk factors for CVD related to adiposity in a population of African origin. Study design: Three empirical studies were undertaken. In study one, 312 adult subjects from three ethnic groups (Afro-Caribbean (n=106), Caucasian (n=165) and South Asian (n=41)) were recruited from a University. Twenty-six (26) of each group were individually matched for age (±3 years) gender and BMI (±2 kg/m2) to allow for comparability. Measures of body composition included height, weight, waist and hip circumferences, skinfold thickness measures, body density and percentagebody fat. In study two, 81 subjects from two ethnic groups (Afro-Caribbean (n=39) and Caucasian (n=42)) were recruited and tested. They were matched for age, gender and BMI using the same criteria as study one. In addition to the body composition measures taken in study one, random non-fasting blood glucose, total cholesterol, triglycerides and blood pressure were taken. In study three, 55 men and 108 women from rural Zimbabwe, 8 men and 17 women from an urban low-density suburb in Harare Zimbabwe, and 28 male and 16 female students from the University of Zimbabwe were recruited and tested. In addition to all measures of body composition in studies one and metabolic analysis in study two, participants’ dietary intake was assessed by food frequency questionnaire and 24hour recall and physical activity was assessed by a physical activity questionnaire. Main findings: • The relationship between BMI and %BF was not the same in all ethnic groups. (aim 1) • There were ethnic differences in the cardiovascular risk predictors between Afro-Caribbean and Caucasian men and women. (aim 1) • It is not recommended that BIA is used as a substitute for TBW estimation in multi-compartment models. (aim 2) • In three groups of Zimbabweans from urban, rural and university locations, a pattern emerged. Amongst women, urban women were at greatest risk, reporting highest values for all variables, followed by rural then university women. Amongst men, urban men were at highest risk, however there were few differences between rural and university men. (aim 3). • Finally, increased WC and dyslipidemia are associated with increasing BMI in populations of African origin. (aim 4) Conclusions: The relationships between overweight, obesity and risk of obesity-related disease differ between different ethnic groups. Moreover, in the groups from Zimbabwe, differences in obesity-related risk were associated with being female and living in urban areas. Therefore, application of universal measures for defining obesity and related diseases may not be applicable to all ethnic groups.

Imaging based muscle density (MD) is associated with poor lower extremity performance, the development of mobility impairments, frailty, and hip fracture. These associations are all related to falls, yet no studies have investigated MD in community dwelling fallers. The primary objective of this study was to determine whether lower leg MD differed between community dwelling elderly women who do and do not report falls. The secondary objective was to determine if lower leg muscle cross sectional area (MCSA), timed up & go (TUG) test, and relative grip strength (RGS; as a ratio to body mass) differed between fallers and non-fallers. Women (N = 135), 60 years or older (mean age 74.1, SD 7.6) were recruited from a random sample of Saskatoon residents. Fallers (n = 36) and Non-fallers (n = 99) were grouped based on 12-month retrospective falls survey response. A peripheral quantitative computed tomography (pQCT) scan of the non-dominant lower leg was acquired to determine MD and MCSA. Participant age, height, weight, TUG test result and RGS were recorded. Between-group differences in mean age, body mass index (BMI), MD, MCSA, TUG and RGS were compared using independent t-tests (P < 0.05). MD and TUG results were transformed to meet the assumption of normality for parametric analysis. Age, BMI, MCSA and RGS did not differ (P > 0.5). Fallers had 3.2% lower MD (P = 0.01) and 15.1% slower TUG scores (P = 0.02), than non-fallers. Muscle density may serve as a physiological marker for the assessment of muscular health and fall risk in community dwelling elderly women.

ABSTRACT Background: Polyunsaturated fatty acids (PUFA) are found in nuts and seeds, salad dressings and vegetable oil and are prone to oxidation during storage and food preparation. Evidence supports that consumption of oxidized lipids promotes atherosclerosis and glucose intolerance in animal models. However there is a dearth of evidence with regard to the amount of oxidized lipids consumed and its association with parameters of adiposity and glucose homeostasis in humans. Objective: The objective of this study is to estimate the amount of oxidized lipids in common foods and the oxidized lipid consumption in the US population using the data from National Health and Nutrition Examination Survey (NHANES) 2005-06. The second objective of this study is to investigate if there is an association between consumption of oxidized lipids with markers of adiposity and glucose tolerance. Methods- Foods with possible high oxidized lipid content were selected from the NHANES food frequency questionnaire. Oxidized lipid content /Peroxide Values (PV) of these foods were determined from published values in the literature. Oxidized lipid consumption was stratified into tertiles to determine the relationship between consumption of oxidized lipids and markers of adiposity. Regression analysis was used to explore to the extent to which body fat % and HOMA- IR scores could be attributed to oxidized lipid intake. Results- The estimated mean daily consumption of oxidized lipids was 0.625 meq/kg of fat for the US population. Estimated mean consumption of oxidized lipids was significantly greater in men compared to women, in children compared to adults and among African Americans compared to other races. In both men and women it was observed that the markers of adiposity like body fat%, waist circumference, triceps skinfold decreased significantly with increased consumption of oxidized lipids. However in women (below 18 years) there was a significant increase in HOMA-IR with increased consumption of oxidized lipids. Conclusion- Increased consumption of oxidized lipids is associated with decreased fat mass but increased glucose intolerance in women, but not in men.

Imaging based muscle density (MD) is associated with poor lower extremity performance, the development of mobility impairments, frailty, and hip fracture. These associations are all related to falls, yet no studies have investigated MD in community dwelling fallers. The primary objective of this study was to determine whether lower leg MD differed between community dwelling elderly women who do and do not report falls. The secondary objective was to determine if lower leg muscle cross sectional area (MCSA), timed up & go (TUG) test, and relative grip strength (RGS; as a ratio to body mass) differed between fallers and non-fallers. Women (N = 135), 60 years or older (mean age 74.1, SD 7.6) were recruited from a random sample of Saskatoon residents. Fallers (n = 36) and Non-fallers (n = 99) were grouped based on 12-month retrospective falls survey response. A peripheral quantitative computed tomography (pQCT) scan of the non-dominant lower leg was acquired to determine MD and MCSA. Participant age, height, weight, TUG test result and RGS were recorded. Between-group differences in mean age, body mass index (BMI), MD, MCSA, TUG and RGS were compared using independent t-tests (P < 0.05). MD and TUG results were transformed to meet the assumption of normality for parametric analysis. Age, BMI, MCSA and RGS did not differ (P > 0.5). Fallers had 3.2% lower MD (P = 0.01) and 15.1% slower TUG scores (P = 0.02), than non-fallers. Muscle density may serve as a physiological marker for the assessment of muscular health and fall risk in community dwelling elderly women.

Background: Liver fibrosis induced by non-alcoholic fatty liver disease causes peri-interventional complications in morbidly obese patients. We determined the performance of transient elastography (TE), acoustic radiation force impulse (ARFI) imaging, and enhanced liver fibrosis (ELF) score for fibrosis detection in bariatric patients. Patients and Methods: 41 patients (median BMI 47 kg/m2) underwent 14-day low-energy diets to improve conditions prior to bariatric surgery (day 0). TE (M and XL probe), ARFI, and ELF score were performed on days -15 and -1 and compared with intraoperative liver biopsies (NAS staging). Results: Valid TE and ARFI results at day -15 and -1 were obtained in 49%/88%and 51%/90%of cases, respectively. High skin-to-liver-capsule distances correlated with invalid TE measurements. Fibrosis of liver biopsies was staged as F1 and F3 in n = 40 and n = 1 individuals. However, variations (median/range at d-15/-1) of TE (4.6/2.6–75 and 6.7/2.9–21.3 kPa) and ARFI (2.1/0.7–3.7 and 2.0/0.7–3.8 m/s) were high and associated with overestimation of fibrosis. The ELF score correctly classified 87.5%of patients. Conclusion: In bariatric patients, performance of TE and ARFI was poor and did not improve after weight loss. The ELF score correctly classified the majority of cases and should be further evaluated.

Background: The relationship between eating frequency (EF) and adiposity is surrounded by controversy. Numerous cross-sectional studies have been performed on the subject, yet the results are mixed. While some of these studies show an inverse relationship between EF and adiposity, this is likely due to underreporting of EF and total energy intake when diets are self-reported. In studies where underreporting was taken into account, EF is positively associated with both energy intake and adiposity. Intervention trials have failed to show a significant effect of EF on energy intake or weight change, but only a small number exist. Objective: In this study, we examined associations among EF, energy intake, and adiposity in free living adults consuming self-selected diets. In conducting this analysis, two common methodological problems in this research area were addressed: 1) the lack of consideration of energy balance fluctuations throughout the day, and 2) a tendency not to account for implausible reporting of energy intake. We hypothesized that individuals with higher EF would have higher BMI, percentage body fat, and energy intake. Additionally individuals with greater fluctuations in energy balance will have higher BMI, percentage body fat, and EF. Methods: We performed a secondary analysis of data collected as part of a previous study in our laboratory on diet and energy regulation (unpublished). One hundred and twenty-six participants were enrolled (62.4 % female, and 75.2% Caucasian), and one participant dropped the study due to pregnancy. Mean ±SD age, BMI, and percentage body fat of the remaining 125 participants were 29.8 ±12.2 years, 24.5±3.9 kg/m2, and 27.8±9.8% respectively. We analyzed one day of dietary intake collected using a multiple pass 24 hour recall. Energy intake was calculated by NDS (Nutrition Data System for Research, version 2011 (n=36) and version 2010 (n=89)). An eating occasion was defined as any occurrence of energy intake > 0 kcal separated by at least 1 hour. EF was defined as the number of eating occasions per day. A specifically designed spreadsheet that generates within-day energy balance was used to produce estimates of hourly energy balance. We also used total energy expenditure measured by doubly labeled water and the Huang et al. (2005)1 method to identify implausible reporters (cutoff for plausibility was reported energy intake (REI) within ±16.8% of TEE) and conducted Pearson’s correlations and regression analysis in both the total sample and a subsample in which implausible energy intake reporters were excluded from analysis. Results: We identified 59.2% of the sample as implausible reporters (n=74; 47 under-reported and 27 over-reported). Mean ±SD EF and energy intake were 4.7±1.5 and 2356±964 kcal in the total sample and 4.8±1.6 and 2371±689 kcal in the plausible sample. In the total sample EF was positively correlated to energy intake among women (r=0.244, p=0.032). No other significant relationships were observed between EF and either energy intake, BMI, or percentage body fat, in the total or plausible sample. In the total sample, maximum energy deficit > 400 kcal in a 24 hours period was significantly and positively correlated with percentage body fat (r=0.211,p=0.019) and negatively correlated with EF (r=-0.243, p=0.007) when controlling for sex and age. Separating the sample by sex we observed significant positive correlation between percentage body fat and maximum energy deficit in men (r=0.382, p=0.009) but not in women. No significant relationships between fluctuations in energy balance and percentage body fat were observed in the plausible sample. Conclusion: No evidence was found to suggest a relationship between EF and adiposity. The significant positive relationships observed between maximum energy deficit and adiposity in the total sample are consistent with previous findings. The number of implausible reporters identified in our analysis supports that over and under-reporting is a major issue associated with self-reporting of dietary intake.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p.104-121

Objectives: To assess the association between serum 25(OH)D and body mass index (BMI) in pre- and early-adolescents and to determine whether this association varies by demographic/clinical characteristics. Methods: Vitamin D status was determined using serum 25(OH)D in healthy pre- and early adolescents in Pittsburgh, PA (deficiency=/mL, insufficiency=12-/mL, sufficiency=≥20 ng/mL). Adiposity was quantified using BMI percentile (normal=<85th, overweight=>85th-95th, obese=>95th). The relationship between serum 25(OH)D and adiposity was assessed in the total population and after stratification by gender, race, Fitzpatrick skin type, age, and Tanner stage. Results: 294 children (mean age 10.2 + 2.1 years; 60% African American; median serum 25(OH)D=27.0 ng/mL) were studied. Serum 25(OH)D was significantly lower in obese (n=72) vs. overweight (n=48) and normal weight (n=171) participants at 23.6, 29.5, and 28.2 ng/mL, respectively; p=0.015. This trend remained significant for early adolescents but did not differ after stratification by other demographic/clinical characteristics. A significant negative correlation was found between BMI and serum 25(OH)D (r = -0.315; p=0.000). Regression analysis predicted that 25% of the variance in serum 25(OH)D levels was attributed to BMI, gender, race, skin type, age, pubertal status, daily vitamin D and calcium intake, sun exposure, and sunscreen use, with Tanner stage being the only significant independent predictor. Conclusions: A significant inverse association between serum 25(OH)D and adiposity was observed in a population of pre- and early adolescents. This relationship was stronger in early adolescents. A meta-analysis to further explore this association in pediatric populations is warranted.