A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in Medicine Johannesburg, 2018. / There has been an increase in the percentage of individuals employed in sedentary occupations over the last 50 years. Prolonged sedentary time has been associated with poorer cardiometabolic health. Interrupting prolonged sedentary activity may attenuate the risk of developing cardiometabolic disease. This study aimed to determine whether prompts delivered via a mobile phone were effective in reducing sedentary behaviour (measured objectively using an Actigraph and activPAL accelerometer) in people with sedentary occupations. Twenty men and women were randomly assigned to either a control or intervention (PROMPT) group. Only participants in the PROMPT group were instructed to interrupt their sedentary behaviour. During the intervention participants in the PROMPT group spent less time in sedentary behaviour (5.5±0.5 hrs/day) during their working day, compared to the control group (6.7±0.6 hrs/day) as measured using the activPAL (p=0.04). There was no association between the intervention and cardiometabolic health variables. There were differences in the outputs of ActiGraph and activPAL accelerometers. Interrupting prolonged sedentary time via mobile phone messages may be an effective strategy in reducing total sedentary time in the workplace. / LG2018

Rationale & Background: During pregnancy, cardiometabolic adaptations occur to sustain fetal growth. Disruptions in maternal cardiometabolic status may arise related to maternal adiposity, dietary deficiencies or excesses, or sedentary behaviours in pregnancy. Clinically, maternal cardiometabolic dysfunction is associated with adverse health outcomes in both mothers and their offspring. We aimed to determine: 1) the contribution of maternal adiposity, diet and physical activity to maternal cardiometabolic status in early pregnancy using biomarkers of lipid and glucose profiles; 2) whether maternal adiposity measured by 4-site sum of skinfold thickness (SFT) or bioelectrical impedance analysis (BIA) yielded similar strength of association with cardiometabolic status. Study Design: Maternal blood samples, anthropometric and body adiposity, dietary and physical activity measures were collected from a subset of pregnant women in early pregnancy (12-17 wk gestation) prior to randomization to the Be Healthy in Pregnancy RCT. Blood samples were analyzed for fasting glucose, insulin, triglycerides, leptin, adiponectin, and C-reactive protein (CRP). Maternal adiposity was assessed by pre- pregnancy body mass index (pBMI) and two indirect quantitative measures of % body fat (BIA and 4-site SFT). Results: Of the 91 subjects (mean age= 31 ± 4 y), 46.2% were overweight/obese by pBMI. For both SFT and BIA, % body fat was positively associated with fasting glucose, insulin, triglyceride, leptin, and CRP concentrations, and negatively associated with adiponectin concentration, although the strength of the associations was greater for SFT than BIA. After adjustment for confounders, maternal adiposity remained significantly associated with all cardiometabolic biomarkers, except for adiponectin and CRP. Dietary polyunsaturated: saturated fat ratio, energy expenditure, high activity level, age, ethnicity and parity were significantly associated with some of the biomarkers. Conclusion: Maternal adiposity was predominantly associated with leptin, insulin, and glucose status in early pregnancy although dietary fat, energy, activity level, age, ethnicity and parity were also significantly associated with some biomarkers. Body fat estimated by SFT or BIA are generally comparable for use as a screening tool for cardiometabolic dysfunction in early pregnancy. In the clinical setting, BIA may be more easily adopted as it is faster and requires fewer technical skills by the operator than SFT measures. / Thesis / Master of Science (MSc)

Given the strong evidence for a beneficial role of vitamin D in diabetes and CVD pathogenesis, and the prevalence of vitamin D deficiency, vitamin D supplementation has been advocated for the prevention of cardiometabolic disease. To provide information on the effects of 5,000IU (125µg) vitamin D3 on cardiometabolic risk, a double blind, RCT in a cohort of overweight and obese UK adult males with plasma 25(OH)D concentration < 75nmol/L for a duration of 8 weeks was conducted. To the best of my knowledge, this is the first RCT to investigate the effect of 5,000IU (125µg) vitamin D3 on cardiometabolic markers in vitamin D insufficient, non-hypertensive and non-diabetic overweight and obese adult males.

Background: Environmental chemicals may interrupt physiological adaptations necessary in pregnancy, contributing to pregnancy complications with health implications for the mother and child. Nutrients may modify the impact of chemical exposures by blocking their absorption or facilitating their excretion. However, the nature, directionality, and implications of these relationships remain unclear. Objectives: We sought to understand: 1) the potential bidirectional nature of the relationship between vitamin D (25-hydroxyvitamin D, 25OHD) and the toxic metals cadmium (Cd) and lead (Pb) in pregnancy; 2) the association between metals (Cd, Pb, arsenic (As), mercury) and preterm birth and the potential modification of that association by 25OHD; and 3) the long-term association of pregnancy complications with maternal cardiometabolic health. Methods: We used data from the Maternal-Infant Research on Environmental Chemicals Study (n=1983) pregnancy cohort, including long-term follow-up approximately 9 years post-pregnancy. We used cross-lagged panel models to determine the direction of the relationship of 25OHD with Cd and Pb in pregnancy, discrete-time survival analysis to examine the association between metals in pregnancy and preterm birth, and multivariable linear regression to investigate the association of pregnancy complications with long-term maternal outcomes. Results: Each doubling in first trimester 25OHD concentrations was associated with 9% (95% CI: -15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. One-unit increases in Pb (μg/dL) and arsenic (μg/L) concentrations in pregnancy were associated with an increased relative risk (RR) of preterm birth (RR_Pb: 1.48, 95% CI: 1.00, 2.20; RR_As: 1.10, 95% CI 1.02, 1.19); the association with Pb was stronger among those with lower 25OHD. Finally, relative to uncomplicated pregnancy, experiencing a pregnancy complication was positively associated with body fat percentage (β=2.6, 95% CI: 0.3, 4.8) and systolic (average increase of 9.0 mm Hg, 95% CI 5.1, 12.8) and diastolic (average increase of 5.5 mm Hg, 95% CI: 2.6, 8.4) blood pressure 9 years later. Conclusions: Nutrient status during pregnancy may affect and interact with environmental chemicals to impact pregnancy outcomes. Future studies should continue to use methods that elucidate the causal direction of associations and evaluate interactions. Chemicals associated with pregnancy complications could have lasting impacts on maternal health.

Background: Telomeres are repetitive, gene-poor regions that cap the ends of DNA and help to maintain chromosomal integrity. Their shortening is caused by inflammation and oxidative stress within the cellular environment and ultimately leads to cellular senescence. Shortened leukocyte telomere length (LTL) is hypothesized to be a novel biomarker for age-related diseases and may therefore be useful in the prediction of cardiometabolic outcomes above conventional risk factors. Methods: A systematic review and meta-analysis was undertaken to summarize existing literature on the association between LTL and myocardial infarction (MI), stroke, and type 2 diabetes (T2D). MEDLINE (1966–present), and EMBASE (1980-present) were last searched on September 9th 2013. Studies were combined using the generic inverse variance method and both fixed and random effects models. Additionally, LTL was measured in 3972 MI patients and 4321 controls from an international study on risk factors for MI (INTERHEART), and 8635 participants from an epidemiological study on dysglycemia and T2D (EpiDREAM) prospectively followed (approximately 3.5 years) for incident cardiometabolic events. Results: Based on current literature, a 1-standard deviation decrease in LTL was significantly associated with stroke (OR=1.21, 95% CI=1.06-1.37; I2=61%), myocardial infarction (OR=1.24, 95% CI=1.04-1.47; I2=68%), and type 2 diabetes (OR=1.37, 95% CI=1.10-1.72; I2=91%). Stratification by measurement technique, study design, study size, and ethnicity explained heterogeneity in certain cardiometabolic outcomes. Within INTERHEART participants, a 1 unit decrease in LTL was associated with an increased risk of MI (OR=2.17, 95% CI=1.74-2.72). Effect estimates were consistent across all ethnic groups (p=0.19). In EpiDREAM a significant association between LTL and T2D or incident cardiometabolic outcomes was not observed. Conclusion: Telomere length appears to be a marker for MI above conventional risk factors. Further research is needed to explain existing heterogeneity in the literature with respect to LTL and T2D. / Thesis / Master of Science (MSc)

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

Diet and lifestyle have changed dramatically in the last few decades, leading to an increase in prevalence of obesity, defined as a body mass index >30Kg/m2, dyslipidaemias (defined as abnormal lipid profiles) and type 2 diabetes (T2D). Together, these cardiometabolic traits and diseases, have contributed to the increased burden of cardiovascular disease, the leading cause of death in Western societies. Complex traits and diseases, such as cardiometabolic traits, arise as a result of the interaction between an individual's predisposing genetic makeup and a permissive environment. Since 2007, genome-wide association studies (GWAS) have been successfully applied to complex traits leading to the discovery of thousands of trait-associated variants. Nonetheless, much is still to be understood regarding the genetic architecture of these traits, as well as their underlying biology. This thesis aims to further explore the genetic architecture of cardiometabolic traits by using complementary approaches with greater genetic and phenotype resolution, ranging from studying clinically ascertained extreme phenotypes, deep molecular profiling, or sequence level data. In chapter 2, I investigated the genetic architecture of healthy human thinness (N=1,471) and contrasted it to that of severe early onset childhood obesity (N=1,456). I demonstrated that healthy human thinness, like severe obesity, is a heritable trait, with a polygenic component. I identified a novel BMI-associated locus at PKHD1, and found evidence of association at several loci that had only been discovered using large cohorts with >40,000 individuals demonstrating the power gains in studying clinical extreme phenotypes. In chapter 3, I coupled high-resolution nuclear magnetic resonance (NMR) measurements in healthy blood donors, with next-generation sequencing to establish the role of rare coding variation in circulating metabolic biomarker biology. In gene-based analysis, I identified ACSL1, MYCN, FBXO36 and B4GALNT3 as novel gene-trait associations (P < 2.5x10-6). I also found a novel link between loss-of-function mutations in the "regulation of the pyruvate dehydrogenase (PDH) complex" pathway and intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and circulating cholesterol measurements. In addition, I demonstrated that rare "protective" variation in lipoprotein metabolism genes was present in the lower tails of four measurements which are CVD risk factors in this healthy population, demonstrating a role for rare coding variation and the extremes of healthy phenotypes. In chapter 4, I performed a genome-wide association study of fructosamine, a measurement of total serum protein glycation which is useful to monitor rapid changes in glycaemic levels after treatment, as it reflects average glycaemia over 2-3 weeks. In contrast to HbA1c, which reflects average glucose concentration over the life-span of the erythrocyte (~3 months), fructosamine levels are not predicted to be influenced by factors affecting the erythrocyte. Surprisingly, I found that in this dataset fructosamine had low heritability (2% vs 20% for HbA1c), and was poorly correlated with HbA1c and other glycaemic traits. Despite this, I found two loci previously associated with glycaemic or albumin traits, G6PC2 and FCGRT respectively (P < 5x10-8), associated with fructosamine suggesting shared genetic influence. Altogether my results demonstrate the utility of higher resolution genotype and phenotype data in further elucidating the genetic architecture of a range of cardiometabolic traits, and the power advantages of study designs that focus on individuals at the extremes of phenotype distribution. As large cohorts and national biobanks with sequencing and deep multi-dimensional phenotyping become more prevalent, we will be moving closer to understanding the multiple aetiological mechanisms leading to CVD, and subsequently improve diagnosis and treatment of these conditions.

The metabolic syndrome has become a major public health challenge world-wide and, at least in the industrialized world, the prevalence of the metabolic syndrome is increasing. There is evidence to show that biological and lifestyle risk factors for metabolic syndrome are present in adolescence, which suggests that the antecedents of the disease may lie in early life. The period of adolescence is characterized by a decline in physical activity (PA; lack of PA is a lifestyle risk factor for metabolic syndrome) and an increase in fat mass deposition (a biological risk factor for metabolic syndrome). Therefore, investigating how the development of these two variables relates to adult cardiometabolic risk is important to fuel early intervention. A factor which has the potential to influence these two risk factors, and thus ultimately the metabolic syndrome, is the timing of biological maturity (i.e. whether an individual is early, average or late maturing when compared to peers of the same age). The influence of biological maturity has largely been overlooked in previous research; therefore, the general objective of this thesis was to investigate the associations between biological maturity, adolescent PA and fat mass development, and young adult cardiometabolic risk. Three studies were necessary to realize this objective, and together help to elucidate the role of biological maturity in the adolescent decline in physical activity, fat development, and the development of adult metabolic syndrome. Ultimately, this information will aid in the development and implementation of interventions to decrease prevalence of metabolic syndrome.<p> Study 1: The purpose of study 1 was to investigate whether observed gender differences in objectively measured PA in children (8 to 13 years) are confounded by biological maturity differences. Methods: Four hundred and one children (194 boys and 207 girls) volunteered for this study. An Actigraph accelerometer was used to obtain 7 consecutive days of minute-by-minute PA data on each participant. Minutes of moderate to vigorous PA per day (MVPA), continuous minutes of MVPA per day (CMVPA), and minutes of vigorous PA per day (VPA) were derived from the accelerometer data. Age at peak height velocity (APHV), an indicator of somatic maturity, was predicted and individuals aligned by this biological age (years from APHV). Gender differences in the PA variables were analyzed using a two-way (gender X age) ANOVA. Results: Levels of PA decreased with increasing chronological ages in both genders (p<0.05). When aligned on chronological age, boys had a higher MVPA at 10 through 13 years, a higher CMVPA at 9 through 12 years, and a higher VPA at 9 though 13 years (p<0.05). When aligned on biological age, PA declined with increasing maturity (p<0.05); however gender differences between biological age groups disappeared. Conclusion: The observed age-related decline in adolescent boys and girls PA is antithetical to public health goals and as such is an important area of research. In order to fully understand gender disparities in PA, consideration must be given to the confounding effects of biological maturity.<p> Study 2: Understanding the influence of biological age (BA) on the decline in PA would better inform researchers about the effective timing of intervention. The purpose of study 2 was to describe the PA levels and perceived barriers to PA of adolescent girls grouped by school grade and biological maturity status (i.e., early or late maturing) within grades. Methods: 221 girls (aged 8-16 years; grades 4-10) wore an Actical accelerometer for 7 days and then completed a semi-structured, open ended questionnaire on perceived barriers to PA over the 7 day period. Predicted APHV and recalled age at menarche were used to assess maturity among the elementary and high school girls, respectively. Maturity and grade group differences in PA were assessed using MANCOVA and independent sample t-test, and barriers to PA using chi squared statistics. Results: Daily minutes spent in MVPA decreased by 40% between grades 4 to 10. Within grade groupings, no differences in PA were found between early and late maturing girls (p>0.05). Grades 4-6 participants cited more interpersonal (i.e., social) barriers. Grades 9-10 participants cited more institutional barriers to PA, primarily revolving around the institution of school. No differences were found in types of barriers reported between early and late maturing girls. Conclusion: Since PA and types of perceived barriers to PA were dependent on grade, future research should work to identify the most salient (i.e., frequent and limiting) barriers to PA by chronological age in youth.<p> Study 3: Although the metabolic syndrome is thought to be mainly a consequence of obesity, the mechanisms underpinning its development are not that well understood. The purpose of study 3 was to examine total body fat mass (FM), trunk FM and PA developmental trajectories (aligned to BA; years from APHV) of individuals categorized as low and high for cardiometabolic risk at 26 years, while investigating biological and lifestyle risk factors. Methods: The sample were 55 males and 76 females from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2007) who were assessed from childhood to young adulthood and had a measure of cardiometabolic risk at young adulthood (26.0 + 2.3 yrs). Height was measured biannually. Total body FM and trunk FM was assessed annually by dual energy-X-ray absorptiometry. PA and dietary intake was evaluated two to three times annually using surveys. Individuals were grouped into maturity status groups (early, average or late) depending on their APHV. Two composite cardiometabolic risk scores were calculated for males and females separately. The first was derived for a sub-sample (N=48) by summing the standardized residuals of inverted high-density lipoprotein cholesterol, homeostasis model assessment for insulin resistance, mean arterial pressure (MAP) and fasting triglyceride levels. A second score was derived for the whole sample by summing the standardized residuals for MAP. Scores for both samples were regressed on to age and adult smoking status. High and low cardiometabolic risk groups were determined based on a sex- specific median split of risk scores. Data were analyzed using random effects models. Models were built in a stepwise procedure with predictor variables added one at a time, using the log likelihood ratio statistic to determine if one model was a significant improvement over the previous one. Results: The final model indicated that once the independent effects of maturity (years from APHV) and height were controlled, the high risk group males and females had significantly (p<0.05) greater total body FM and trunk FM development at all ages. No association was found between young adult cardiometabolic risk and development of PA. Furthermore, in general, timing of biological maturity was not associated with development of PA or FM. Conclusion: Young adults at higher cardiometabolic risk have greater body fat as early as 8 years of age, which lends support to early intervention.<p> General Conclusions: Adolescence has been highlighted as a critical period for the development of adult disease, such as the metabolic syndrome. Results from this thesis support this contention by showing a decrease in PA (by both chronological and biological age) in males and females across adolescence. It further showed that an increase in total and central fatness during adolescence may be critical for the development of the metabolic syndrome in adulthood. Timing of biological maturity, in general, was not shown to have an independent impact on adolescent or young adult PA, adolescent perceived barriers to PA, fat mass development, or young adult cardiometabolic risk. However, further research is required before definitive conclusions can be made about the short and long term impacts of timing of biological maturity on health.

The metabolic syndrome has become a major public health challenge world-wide and, at least in the industrialized world, the prevalence of the metabolic syndrome is increasing. There is evidence to show that biological and lifestyle risk factors for metabolic syndrome are present in adolescence, which suggests that the antecedents of the disease may lie in early life. The period of adolescence is characterized by a decline in physical activity (PA; lack of PA is a lifestyle risk factor for metabolic syndrome) and an increase in fat mass deposition (a biological risk factor for metabolic syndrome). Therefore, investigating how the development of these two variables relates to adult cardiometabolic risk is important to fuel early intervention. A factor which has the potential to influence these two risk factors, and thus ultimately the metabolic syndrome, is the timing of biological maturity (i.e. whether an individual is early, average or late maturing when compared to peers of the same age). The influence of biological maturity has largely been overlooked in previous research; therefore, the general objective of this thesis was to investigate the associations between biological maturity, adolescent PA and fat mass development, and young adult cardiometabolic risk. Three studies were necessary to realize this objective, and together help to elucidate the role of biological maturity in the adolescent decline in physical activity, fat development, and the development of adult metabolic syndrome. Ultimately, this information will aid in the development and implementation of interventions to decrease prevalence of metabolic syndrome.<p> Study 1: The purpose of study 1 was to investigate whether observed gender differences in objectively measured PA in children (8 to 13 years) are confounded by biological maturity differences. Methods: Four hundred and one children (194 boys and 207 girls) volunteered for this study. An Actigraph accelerometer was used to obtain 7 consecutive days of minute-by-minute PA data on each participant. Minutes of moderate to vigorous PA per day (MVPA), continuous minutes of MVPA per day (CMVPA), and minutes of vigorous PA per day (VPA) were derived from the accelerometer data. Age at peak height velocity (APHV), an indicator of somatic maturity, was predicted and individuals aligned by this biological age (years from APHV). Gender differences in the PA variables were analyzed using a two-way (gender X age) ANOVA. Results: Levels of PA decreased with increasing chronological ages in both genders (p<0.05). When aligned on chronological age, boys had a higher MVPA at 10 through 13 years, a higher CMVPA at 9 through 12 years, and a higher VPA at 9 though 13 years (p<0.05). When aligned on biological age, PA declined with increasing maturity (p<0.05); however gender differences between biological age groups disappeared. Conclusion: The observed age-related decline in adolescent boys and girls PA is antithetical to public health goals and as such is an important area of research. In order to fully understand gender disparities in PA, consideration must be given to the confounding effects of biological maturity.<p> Study 2: Understanding the influence of biological age (BA) on the decline in PA would better inform researchers about the effective timing of intervention. The purpose of study 2 was to describe the PA levels and perceived barriers to PA of adolescent girls grouped by school grade and biological maturity status (i.e., early or late maturing) within grades. Methods: 221 girls (aged 8-16 years; grades 4-10) wore an Actical accelerometer for 7 days and then completed a semi-structured, open ended questionnaire on perceived barriers to PA over the 7 day period. Predicted APHV and recalled age at menarche were used to assess maturity among the elementary and high school girls, respectively. Maturity and grade group differences in PA were assessed using MANCOVA and independent sample t-test, and barriers to PA using chi squared statistics. Results: Daily minutes spent in MVPA decreased by 40% between grades 4 to 10. Within grade groupings, no differences in PA were found between early and late maturing girls (p>0.05). Grades 4-6 participants cited more interpersonal (i.e., social) barriers. Grades 9-10 participants cited more institutional barriers to PA, primarily revolving around the institution of school. No differences were found in types of barriers reported between early and late maturing girls. Conclusion: Since PA and types of perceived barriers to PA were dependent on grade, future research should work to identify the most salient (i.e., frequent and limiting) barriers to PA by chronological age in youth.<p> Study 3: Although the metabolic syndrome is thought to be mainly a consequence of obesity, the mechanisms underpinning its development are not that well understood. The purpose of study 3 was to examine total body fat mass (FM), trunk FM and PA developmental trajectories (aligned to BA; years from APHV) of individuals categorized as low and high for cardiometabolic risk at 26 years, while investigating biological and lifestyle risk factors. Methods: The sample were 55 males and 76 females from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2007) who were assessed from childhood to young adulthood and had a measure of cardiometabolic risk at young adulthood (26.0 + 2.3 yrs). Height was measured biannually. Total body FM and trunk FM was assessed annually by dual energy-X-ray absorptiometry. PA and dietary intake was evaluated two to three times annually using surveys. Individuals were grouped into maturity status groups (early, average or late) depending on their APHV. Two composite cardiometabolic risk scores were calculated for males and females separately. The first was derived for a sub-sample (N=48) by summing the standardized residuals of inverted high-density lipoprotein cholesterol, homeostasis model assessment for insulin resistance, mean arterial pressure (MAP) and fasting triglyceride levels. A second score was derived for the whole sample by summing the standardized residuals for MAP. Scores for both samples were regressed on to age and adult smoking status. High and low cardiometabolic risk groups were determined based on a sex- specific median split of risk scores. Data were analyzed using random effects models. Models were built in a stepwise procedure with predictor variables added one at a time, using the log likelihood ratio statistic to determine if one model was a significant improvement over the previous one. Results: The final model indicated that once the independent effects of maturity (years from APHV) and height were controlled, the high risk group males and females had significantly (p<0.05) greater total body FM and trunk FM development at all ages. No association was found between young adult cardiometabolic risk and development of PA. Furthermore, in general, timing of biological maturity was not associated with development of PA or FM. Conclusion: Young adults at higher cardiometabolic risk have greater body fat as early as 8 years of age, which lends support to early intervention.<p> General Conclusions: Adolescence has been highlighted as a critical period for the development of adult disease, such as the metabolic syndrome. Results from this thesis support this contention by showing a decrease in PA (by both chronological and biological age) in males and females across adolescence. It further showed that an increase in total and central fatness during adolescence may be critical for the development of the metabolic syndrome in adulthood. Timing of biological maturity, in general, was not shown to have an independent impact on adolescent or young adult PA, adolescent perceived barriers to PA, fat mass development, or young adult cardiometabolic risk. However, further research is required before definitive conclusions can be made about the short and long term impacts of timing of biological maturity on health.

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of death and often develop due to obesity-induced complications including hyperlipidemia, elevated blood pressure (BP), inflammation, and oxidative stress. Epidemiological, animal model, and cell culture studies indicate that citrus, and grapefruit specifically, exert cardiovascular health benefits, likely due to the high flavonoid content in citrus fruits. Grapefruit and/or isolated grapefruit flavonoids elicit cardiovascular benefits via improvements in lipid metabolism and endothelial reactivity, and by antioxidant and anti-inflammatory actions. The aim of this work was to determine the role of six-week daily consumption of grapefruit on weight, lipid, and BP control as well as inflammatory and oxidative stress markers in overweight/obese adults. Further, we sought to evaluate the acute, postprandial effects of grapefruit consumption on metabolic, inflammatory, and oxidative stress markers in response to a high fat, high calorie (HFHC) double meal challenge. Participants were randomized to either a grapefruit group (n=42) in which they consumed 1.5 grapefruit/day for six weeks or to a control condition (n=32). Ten participants who completed the feeding trial also participated in the postprandial study. On two test days participants consumed a HFHC meal for breakfast and again for lunch. A ruby red grapefruit was consumed with breakfast on the first test day. Blood samples were collected at baseline and for the subsequent eight hours on each day. In the feeding trial, grapefruit consumption resulted in reductions in waist circumference (p<0.001), systolic BP (p=0.03), total cholesterol (p=0.001), and LDL-cholesterol (p=0.021) compared to baseline values. F2-isoprostanes and hsCRP values were nonsignificantly lower in the grapefruit vs. control arm following the intervention (p=0.063 and p=0.073, respectively). In the postprandial evaluation, insulin concentrations were significantly higher 30 minutes (p=0.007) and 2 hours (p=0.025) post HFHC + grapefruit meal consumption vs. HFHC alone. HFHC + grapefruit intake resulted in lower IL-6 concentrations after two hours (p=0.017) and lower F2-isoprostanes after 5 hours (p=0.0125). These findings suggest that regular grapefruit consumption may reduce CVD risk by targeting many of the risk factors and pathogenic factors involved in endothelial dysfunction. However, this dietary change alone is unlikely to result in significant CVD risk reduction.