Cardiometabolic diseases are the leading causes of worldwide mortality, of which metabolic syndrome is a major contributor. Increased sedentary behavior and decreased physical activity have been independently associated with increased risk of developing metabolic syndrome and subsequent maladies. Likewise, the development of more contemporary methodologies of measuring metabolic syndrome allow for a more nuanced examination of risk. However, these new methodologies lack extensive utilization among the physical activity epidemiology literature. The scarcity of research incorporating the independent relations between sedentary behavior, physical activity, and contemporary methodologies to measure metabolic syndrome warrants additional investigation. This dissertation aimed to further discern these relations using three different cohort data sets. Data from the National Health and Nutritional Examination Survey (NHANES), the Jackson Heart Study (JHS), and the Coronary Artery Risk Development in Young Adults (CARDIA) Study were utilized to further elucidate the relations between sedentary behavior, physical activity, and metabolic syndrome in three separate studies. The studies observed the majority of waking hours were spent engaged in sedentary behaviors; although, each cohort also appeared to meet the Physical Activity Guidelines for Americans. Metabolic syndrome positive individuals from NHANES engaged in similar amounts of physical activity as the general population. While the diversity of physical activity type was less, the physical activities engaged in were typically at the same prevalence among metabolic syndrome positive and the general populations. Sedentary behaviors were associated with increased metabolic syndrome severity score, but this relation was attenuated when moderate-to-vigorous physical activity and cardiorespiratory fitness were added to the model for both JHS and CARDIA studies. Decreasing sedentary time and with an equivalent amount of physical activity, of any intensity, is beneficial for cardiometabolic health. Understanding which physical activities subpopulations engage in can be paired with culturally competent interventions to increase physical activity engagement. Exceeding the minimum requirements for the Physical Activity Guidelines for Americans can produce increases in cardiorespiratory fitness, which have an independent positive impact on cardiometabolic health. Strategies should aim to increase physical activity among sedentary individuals, while limiting sedentary time among those physically active.

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Rationale & Background: Gaining excessive adiposity in pregnancy is associated with altered cardiometabolic profile and adverse pregnancy outcomes. Lifestyle interventions may reduce excess weight gain, but the effect on fat gain is unclear. Our study explored this question by 1) comparing measures of body fat (BF) by bioelectrical impedance analysis (BIA) and 4-site skinfold thickness (SFT); 2) assessing the impact of a nutrition+exercise intervention on adiposity changes; 3) elucidating associations between adiposity changes and cardiometabolic biomarkers and adverse pregnancy outcomes. Study Design: Participants randomized to receive a high dairy protein diet and exercise program (intervention) or standard care (control) in the Be Healthy in Pregnancy RCT (NCT 01689961) had adiposity measured at 12-17, 26-28, and 36-38 weeks gestation by BIA (%BF) and SFT (sum and %BF), and at 6 months postpartum also by DXA. Fasted blood samples collected at 12-17 and 36-38 weeks gestation were analyzed for glucose, lipid profile, insulin, leptin, adiponectin, and CRP. Pregnancy outcomes were abstracted from medical charts. Results: In 181 participants, BIA %BF and SFT %BF had good agreement in early pregnancy and postpartum, but low agreement in late pregnancy. Adiposity changes across pregnancy were similar between study arms but were greater in normal weight compared to overweight women. Insulin and leptin were negatively associated with change in SFT (sum and %BF). Triglycerides were negatively associated with change in BIA %BF, while HDL was positively associated. Neither caesarean section nor operative vaginal delivery were associated with adiposity change. Conclusion: Adiposity measured by sum of SFT and BIA %BF increased across pregnancy but was not influenced by the diet+exercise intervention. Associations of adiposity change with cardiometabolic biomarkers varied between measurement tools. The lack of adiposity measurement tools appropriate across pregnancy and in clinical settings presents a concern for assessing clinical responses to adiposity change across pregnancy. / Thesis / Master of Science (MSc) / Pregnancy is associated with a natural gain in body fat, but it can reach excessive amounts. Excess body fat is of clinical consequence as it is associated with poor cardiovascular health and abnormal pregnancy outcomes. Improving diet and physical activity habits may reduce excess weight gain, but little is known about how it influences fat gained during pregnancy. In our study body fat gain during pregnancy was similar between the lifestyle intervention and control groups. However, entering pregnancy with greater BMI was associated with less fat gain during pregnancy. Changes in body fat influenced cardiovascular blood markers, but results differed between body fat assessment tools. We also found that methods to measure body fat produce different results at different stages of pregnancy. Our findings provide insight on the factors that influence fat gain during pregnancy and highlight the need for better tools to measure body fat accurately in pregnancy.

京都大学 / 新制・課程博士 / 博士(ゲノム医学) / 甲第25211号 / 医博JD第3号 / 新制||医JD||1(附属図書館) / 京都大学大学院医学研究科ゲノム医学国際連携専攻 / (主査)教授 村川 泰裕, 教授 平井 豊博, 教授 William Foulkes (ﾏｷﾞﾙ大学), 准教授 George Thanassoulis (ﾏｷﾞﾙ大学), 教授 Krzysztof Kiryluk (ｺﾛﾝﾋﾞｱ大学) / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

The principle aims of this work were two fold; firstly to identify the current dietary intakes (specifically dietary glycaemic carbohydrate (CHO)) and physical activity (PA) and cardiorespiratory fitness (CRF) levels of a UK, postpubertal, adolescent population (n = 105) and assess the relationship between these factors, adiposity and cardiometabolic health. Diet and health relationships were assessed whilst accounting for energy misreporting and controlling for levels of PA and CRF. The effect of excluding dietary misreporters on the associations between glycaemic CHO and health was assessed whilst comparing an established technique (the Goldberg equation) to a novel approach (the ratio of energy intake (EI) to energy expenditure (EE)), which utilised RT3 accelerometry data (EI:EE(RT3)). Associations of PA and metabolic risk factors were also assessed whilst comparing two child specific PA thresholds for the assessment of PA subcomponents. Secondly, the impact of a flexible, ad libitum, low GI dietary intervention on cardiometabolic health was examined in an „at risk‟, overweight, postpubertal, adolescent population. Glycaemic index (GI) but not glycaemic load (GL) was shown to be associated significantly with anthropometric measures (body mass index (BMI), waist circumference (WC)) and adiposity (body fat percentage (BF%)) in this general group of post-pubertal adolescents from Bedfordshire. When adjusting for dietary intake, CRF was also associated with adiposity but PA was not. The prevalence of misreporting varied depending on the method used to assess the validity of dietary intakes; between 23% and 31% increasing to 62.1% (in overweight) of adolescents under reported energy intakes and up to 11.1% over reported. The novel application of a triaxial accelerometer to measure EE resulted in more under and over reporters being identified than when compared to the widely used Goldberg equation. Increased dietary GI was associated with increased odds of having a high WC; however, associations between GL and other risk factors were less clear; no associations with risk were observed. Excluding dietary misreporters from analysis had important implications for these associations. Only after removal of misreporters by EI:EE(RT3) was a borderline significant positive association between GL and blood glucose (BG) revealed using multiple analysis of covariance (MANCOVA), that was not present in prior analyses. Increased GI (moderate vs low GI intake) was significantly associated with reduced high density lipoprotein cholesterol (HDL) and increased triglyceride (TG) levels (borderline significant) after removal of misreporters. In addition, using different PA thresholds to assess PA intensity resulted in different relationships between PA subcomponents and metabolic risk factors. Regardless of the threshold used, evidence suggested that limiting sedentary (SED) behaviour and engaging in moderate to vigorous PA (MVPA) is beneficial for blood pressure (BP) in this adolescent population. Additionally, irrespective of the threshold utilised, higher levels of vigorous PA (VPA) were associated with reduced odds of having a high clustered risk score and the associations observed between CRF and risk factors were stronger than those observed with PA. Despite a lack of significant improvement in individual metabolic risk factors as a result of the low GI (LGI) dietary intervention, there was a significant reduction in clustered risk score for the LGI group at week 12. A borderline significant improvement in glycated haemoglobin (HbA1c) was also observed as a result of the LGI intervention compared to those in the control group. Conversely, there appeared to be an unfavourable effect of the LGI diet on fasting insulin levels and thus the diet‟s impact on health overall is unclear. The small sample size of this randomised controlled trial (RCT) means that caution is required when interpreting the results. These data suggest that future research in this age group should target improvements in CRF and a lower dietary GI to reduce adiposity. Controlling for dietary misreporting appears to have a significant impact on associations of glycaemic CHO and cardiometabolic health and should be an important consideration of future research. The low GI intervention may be an effective approach for reducing glycaemic CHO, whilst maintaining a healthy macronutrient intake, in comparison to more restricted dietary regimens published in the literature. However, the impact of this regime needs to be confirmed utilising a larger sample of adolescents. This may provide a useful approach for future research aiming to assess the impact of reduced GI and GL.

Whilst high levels of cardiorespiratory fitness and physical activity may protect against cardiometabolic risk factor clustering, evidence suggests these outcomes are below optimal in English youths. Adolescence is a key stage in health behaviours development, and thus represents an opportunity for interventions aiming to improve the cardiometabolic health, fitness and activity levels of this population. Recently, there has been growing interest in the efficacy of low-volume high-intensity interval training (HIT) as a time efficient way of improving health and fitness outcomes in adults. Contrastingly, the effects of low-volume HIT in adolescents remains relatively unknown. The first aim of this programme therefore was to develop a novel school-based low-volume HIT intervention. The second was to determine the effectiveness of this model for improving the cardiometabolic health, cardiorespiratory fitness and physical activity levels of adolescents. Study one examined adolescents’ views towards high-intensity exercise, and the proposed low-volume HIT intervention. This data was used to design the novel low-volume HIT model. In Study 2, participants’ heart rate and perceived exertion responses to three prototype prescriptions of low-volume HIT, based on boxing, dance and football were examined. Here, it was indicated that these activities were capable of eliciting a high-intensity training response (~90% of maximum heart rate). Study 3 incorporated the main intervention, which examined the effect of a 10-week multi-activity low-volume HIT intervention (named Project FFAB [Fun Fast Activity Blasts]) on various health and fitness outcomes in adolescents. Here, beneficial effects were detected in the intervention participants compared to the controls for triglycerides, waist circumference, lipid accumulation product and daily moderate-to-vigorous physical activity. Study 4 assessed the fidelity of the intervention, and found that this had been largely upheld. Collectively therefore, it appears that Project FFAB represents a viable strategy for improving aspects of cardiometabolic health and physical activity levels in adolescents.

L’inflammation de bas grade est un trait commun aux maladies cardiométaboliques (CMDs). Dans l’obésité et le diabète de type-2 (DT2) en particulier, l’insulino-résistance a été associée à une inflammation dans plusieurs tissus. L’objectif de ce travail est d’évaluer les interactions entre les altérations des cellules immunitaires et les perturbations du métabolisme dans les CMDs. Dans une première étude, nous avons étudié l’immunité intestinale et la production cytokinique des lymphocytes T (LT) jéjunaux de sujets minces et obèses et évalué la relation fonctionnelle entre LT et entérocytes. Nous montrons que la densité des LT est augmentée dans la muqueuse dans l’obésité et que l’augmentation de la production de cytokines par les LT de sujets obèses induit une résistance à l’insuline sur les entérocytes in vitro. Dans une deuxième étude, nous avons caractérisé les cellules MAIT (mucosal-associated invariant T cells), une sous-population de LT qui reconnait des métabolites bactériens dérivés de la vitamine B, dans le sang de 5 groupes de patients présentant différentes CMDs par rapport à des sujets contrôles. Dans tous les groupes de patients, nous observons une diminution des cellules MAIT circulantes qui est corrélée avec l’HbA1c. Nous montrons ex vivo que cette diminution pourrait être liée à une plus forte apoptose provoquée par une glucotoxicité. Nos résultats indiquent que l’environnement immunitaire intestinal pourrait participer aux perturbations métaboliques locales et systémiques dans l’obésité humaine. De plus, l’abondance de certaines cellules immunitaires, comme les MAIT, pourrait servir de marqueur précoce de la dysfonction cardiométabolique. / A common feature between cardiometabolic diseases (CMDs) is a state of chronic low-grade inflammation. In obesity and type-2-diabetes (T2D) notably, insulin resistance has been linked to inflammation in several tissues. The objective of this project is to evaluate the interactions between immune cell alterations and metabolic perturbations in CMDs. In a first study, we investigated intestinal immunity and cytokine production of intestinal T cells in a cohort of lean and obese subjects and evaluated the functional relationship between T cells and enterocytes. We demonstrated that T cell density and cytokine production was increased in the jejunal mucosa of obese subjects and promoted insulin resistance in enterocytes in vitro. In a second study, we characterized mucosal-associated invariant T (MAIT) cells, a subset of T cells recognizing bacterial vitamin B derivatives, in 5 groups of patients with different forms CMDs (metabolic syndrome, obesity, T2D, coronary artery disease with or without heart failure) compared to healthy subjects. We demonstrated that MAIT cell decrease is correlated with HbA1c and is a common feature in all CMD groups. In an ex vivo study, we show that their depletion in the blood could be explained by a higher propensity to apoptosis under high glucose concentrations. Altogether, our findings suggest that the jejunal immune microenvironment could participate in local and systemic metabolic perturbations in human obesity. We also demonstrate that the abundance immune cells, such as circulating MAIT cells could serve as an early marker of cardiometabolic dysfunction.

Obesity, elevated blood pressure and dyslipidemia are highly prevalent in Hispanic children. Compared to their non-Hispanic White peers, Hispanic children experience higher prevalence of obesity and hypertension. The Hispanic population in Tennessee has been growing, with about a tenth of newborn babies being Hispanic. This study aimed to: 1. Examine the influence of sociodemographic factors on Hispanic children’s cardiometabolic risk; 2. Assess the relationship between food group intake and cardiometabolic risk in Hispanic children; and 3. Evaluate the efficacy of non-traditional biomarkers for detecting cardiometabolic risk in Hispanic children. Data for the study came from a larger cross-sectional pilot study of metabolic syndrome in Hispanic children attending a community health center in Johnson City, TN. Descriptive and multiple logistic regression analyses were used. The prevalence of overweight and elevated blood pressure were 40.7% and 31.0% respectively. Children of obese mothers were more likely than children of mothers with normal body mass index to engage in less than three days of at least 60 minutes of vigorous physical activity (PA) per week (OR: 6.47: 95% CI: 1.61-26.0). Children whose mothers did not engage in moderate PA were more likely to have elevated blood pressure (OR: 2.50, 95%CI: 1.02-4.53); and to engage in less than three days of at least 60 minutes of vigorous PA per week (OR: 2.92, 95% CI: 1.18-7.24), than children whose mothers engaged in moderate PA. Children generally exceeded fruit and legume intake recommendations, but did not meet vegetable, wholegrain, dairy and fiber recommendations. Higher legume (OR: 0.052, 95% CI: 0.04-0.64), dairy (OR: 0.61, 95% CI: 0.37-0.99) and fiber intake (OR: 0.88, 95% CI: 0.81-0.96) were protective against elevated blood pressure, but only fruit intake was protective against overweight (OR: 0.93, 95% CI: 0.87-0.99). Leptin, C-peptide and TNF-α showed significant positive correlations with cardiometabolic risk factors. The optimal cut-offs for detecting three or more cardiometabolic risk factors were: leptin, 5.95 ng/ml, C-peptide, 0.73 ng/; and TNF-alpha, 4.28 pg/ml. Helping mothers to achieve and maintain a healthy BMI and promoting children’s consumption of more vegetables, fruits, dairy and fiber could help reduce cardiometabolic risk in Hispanic children.

Background. The diagnosis of metabolic syndrome is currently based on synthesizing measurements on five different biochemical and anthropometric scales. The logistics involved makes it less than an ideal screening test of cardiometabolic risk. Adipocytokines, c-peptide and ghrelin have emerged as important non-traditional biomarkers for understanding cardio-metabolic risk, and offer potential as tests of cardiometabolic risk. However, optimal sensitivity and specificity cut-offs of non-traditional biomarkers for detecting cardiometabolic risk are scarce, especially in pre-adolescent ethnic minorities. Objective. To assess the efficacy of 7 non-traditional biomarkers for detecting 3 or more cardiometabolic risk factors in pre-adolescent Hispanic children. Methods. The study population consisted of a healthy control group of 23 children and an at-risk group of 15 children aged 2-10 years with 3 or more cardiometabolic risk factors (blood pressure>=90th percentile; waist circumference >=90th percentile; triglycerides>=95th percentile; and HDL<5th >percentile) who were recruited as part of a larger pilot study of metabolic syndrome in Hispanic children receiving well-child care at a community health center in Johnson City, TN, from June 2015 to September 2016. T-test, Mann-Whitney U and Chi-squared tests were used to assess differences in characteristics of the two groups. Spearman’s correlation analysis was used to assess the relationship between biomarkers and cardiometabolic risk factors. ROC analysis and the Youden’s J statistic=maximum (sensitivity +(specificity-1)) were used to determine biomarker cut-off for optimal sensitivity and specificity. Data analysis was performed using SAS 9.4. Results. The mean age of the sample was 6.48 years (SD=2.74). About half of the sample were girls (50.5%). The at-risk group had significantly higher systolic blood pressure, triglyceride levels, waist circumference, leptin and C-peptide levels, but significantly lower HDL-C levels than participants in the control group. Leptin [r (38) = 0.3, p

Exposure to environmental pollutants poses numerous risk factors for human health, including increasing incidence of cardiovascular disease and diabetes. Persistent organic pollutants, such as polychlorinated biphenyls (PCBs) have been strongly linked to the development of these chronic inflammatory diseases and the primary route of exposure is through consumption of contaminated food products. Thus, the gastrointestinal tract is susceptible to the greatest levels of these pollutants and is an important facet to study. The first two hypotheses of this dissertation tested that exposure to PCBs disrupts gut microbiota directly (in vitro) and within a whole body system. PCB exposure disrupted microbial metabolism and production of metabolites (i.e. short chain fatty acids) in vitro. These disruptions in microbial populations were consistent in our mouse model of cardiometabolic disease, where we observed reductions in microbial diversity, an increase in the putative pro-inflammatory ratio of Firmicutes to Bacteroidetes, and reductions in beneficial microbial populations in exposed mice. Furthermore, observed greater inflammation was observed both within the intestines and peripherally in PCB exposed mice as well as disruptions in circulating markers associated with glucose homeostasis. Nutritional interventions high in prebiotic dietary fiber such as inulin may be able to attenuate the toxic effects of pollutant exposure. To test the hypothesis that consumption of the prebiotic inulin can decrease PCB-induced disruption in gut microbial and metabolic homeostasis, LDLr-\- mice were fed a diet containing inulin and exposed to PCB 126. Mice fed an inulin-containing diet and exposed to PCBs exhibited improved glucose tolerance, lower hepatic inflammation and steatosis, and distinct differences in gut microbial populations. Overall, these data suggests that nutritional intervention, specifically prebiotic consumption, may reduce pollutant-induced disease risk.