Rising obesity rates have generated serious policy concern and public interest. Along with biological and genetic factors contributing to weight gain, dietary and physical activity behaviours are considered the main determinants of individual body weight. In order to tackle the increasing obesity problem and change individual behaviour, effective policy interventions need to be developed which target specific groups within the population. Economic frameworks that have been designed to model individual choices can be applied to improve the understanding of how individual characteristics and socio-economic factors affect weight-related behaviours and body weight. This thesis uses data from the Scottish Health Survey and the HILDA (Household, Income, and Labour Dynamics in Australia) survey to empirically analyse (1) if average BMI and socio-economic characteristics differ across combinations of weight-related behaviours, (2) how diet and physical activity behaviours, as well as their determinants, can be adapted to explain BMI on average, (3) how determinants of BMI impact differently across a conditional BMI distribution, and (4) to what degree a change in BMI over time can be explained by changing influences. While previous economic research did not consider the combined effect of dietary and physical activity behaviours on body weight, this work will investigate the relationship between the weight-related behaviours and individual BMI on average and across the conditional BMI distribution to identify areas for policy interventions. Results indicate that an increase in individual physical activity is an effective measure to target individual weight. Although the energy balance framework suggests a promotion of both weight-related behaviours and traditional weight management measures promote a reduction in caloric intake, the analyses have shown that physical activity is the predominant behaviour regarding the influence on individual BMI (compared to individual diet measured by quality proxies rather than the overall caloric intake).

Reducing obesity remains a public health priority of urgent necessity. In an effort to address this need and plan future health interventions, a survey of obesity-related knowledge and beliefs was administered in a small population of Hispanic women in an urban Phoenix health center. This paper describes the project design and project findings. A cross sectional univariate descriptive design was conducted by administration of Obesity Risk Knowledge Survey (ORK-10) and the Obesity Belief Scale (OBS). Self-administered surveys were provided to patients during regularly scheduled health visits at the Wesley Health Center in Downtown Phoenix. Participants included 12 Hispanic women aged 18 years or older, with a body mass index greater than 25. Results from the OBS scale were analyzed to evaluate whether respondents held positive or negative beliefs in the OBS subscales. The Theory of Planned Behavior then served as a model to guide evaluation of the findings from the OBS subscales. Results of the ORK-10 were calculated for overall score, with higher scores associated with greater obesity knowledge (range 2 - 8, (mean (S.D.) = 5.3(1.8)). Findings from the OBS subscales were assess on 7 point Likert scale. The Health Beliefs subscale responses were overwhelmingly positive while the Social and Aesthetic Beliefs and Cost subscale scores were found to have negative beliefs. Results from the survey did not reflect positive intention among the participants. While attitude toward the behavior was overwhelmingly positive among survey participants, social behavior norms, and perceived control were reflected negatively by survey responses. Based on The Theory of Planned Behavior negative responses in any of these categories suggests that population has negative intention and is thus incapable of successful behavior change.

Obesity is recognized as a risk factor for adverse pregnancy outcomes. Maternal obesity prevalence has increased in parallel with that in the general population and is associated with an increase in morbidity and mortality for both mother and baby. Obese mothers are more likely to develop gestational diabetes, hypertensive disorders including preeclampsia, thromboembolic complications, miscarriage, and have an increased need for induction of labour. Babies born from obese mothers can be abnormally large (macrosomia) or small for gestational age, and have a higher risk of perinatal death and congenital malformation. Pregnancy induces marked and dynamic changes in energy metabolism, however, the direct effects of pregnancy adipose tissue biology in both normal lean and obese women is still largely unknown. The aim of this thesis was to delineate novel mechanisms by which pregnancy affects adipose tissue biology, and thus infer how obesity might adversely affect pregnancy outcomes. We used an animal model of obesity during pregnancy in which mice were given a high fat diet (HF) to make them obese. We identified that pregnancy was associated with an unexpected curtailment of visceral (mesenteric) adipose tissue mass in HF mice and with an attenuation, rather than worsening of the metabolic impairment expected from the combination of excess dietary fat and insulin resistance/glucose intolerance of pregnancy. To determine the underlying molecular mechanism contributing to this phenotype global gene expression microarray with subsequent pathway analysis and qRT-PCR validation was employed within the visceral adipose tissue. In visceral fat of HF pregnant mice, gene pathways for de novo lipogenesis and lipid storage, inflammation, retinol metabolism, insulin like growth factor and estrogenic signaling showed altered regulation. Given the known role of estrogen on adipose tissue and inflammatory cell function, a hypothesis was generated that altered estrogen receptor (ER)α expression/activation/increased estradiol presence within mesenteric fat formed a unifying molecular mechanism underlying the altered adipose biology and relative amelioration of the metabolic phenotype in HF pregnant mice. To test the ER α hypothesis, a female clonal adipocyte cell line, Chub-S7, and primary visceral and subcutaneous adipocytes from pregnant obese and lean patients were treated with the ERα selective agonist, PPT. PPT downregulated mRNA levels of key genes involved in de novo lipogenesis (ME1, FANS and SCD1 Dgat2), consistent with a direct role for ERα activation in curtailment of fat expansion. Although the primary human study lacked sufficient power to adequately address the hypothesis, PPT significantly suppressed SCD1 mRNA levels in visceral adipocytes of lean women. In parallel with the curtailment of mesenteric fat expansion, HF pregnant mice were found to have increased liver weight and liver triglyceride content. However, this “fatty liver” phenotype was not associated with increased mRNA levels of genes involved in hepatic triglyceride uptake or de novo lipogenesis. This increase in liver triglycerides may be due to an excessive influx of fatty acids from mesenteric fat through the portal vein. In conclusion, pregnancy in obese animals is associated with a beneficial curtailment in mesenteric fat expansion, normalization of metabolic disturbances and reduced adipose inflammation. Increased ERα activation within adipocytes may play a critical role in this phenotype.

No description available.

Research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science (MSc) in Epidemiology in the field of Epidemiology and Biostatistics / Obesity is an emerging problem in South Africa, particularly in women for whom prevalence rates well above 40% have been reported. Parallel to this health problem, South Africa continues to experience relatively high poverty levels of 10.5% to 48.0%. The aim of this study was to estimate the prevalence of obesity and low social economic status (SES) levels at Agincourt Health and Socio-Demographic Surveillance System site (AHDSS). The study also sought to investigate the association between low SES and obesity at AHDSS. Materials and methods This was a secondary data analysis of the original Na Nakekela HIV/Non communicable disease (NCD) study conducted at AHDSS from August 2010 to May 2011. Included in the study presented in this report were residents of AHDSS aged 15 years or older during this time period. Data from 4 502 individuals (2 683 females and 1 819 males) were analysed. Age-specific prevalences of obesity (body mass index ≥ 30kg/m2), and central obesity (waist hip ratio ≥1.0 and ≥0.85 in men and women, respectively), stratified by sex and SES, were calculated. SES was assessed by ascertaining the household assets of AHDSS residents and assigning a weighted score to the household assets, using multiple correspondence analysis (MCA). The household score was then computed and used to classify the population into SES categories. The relative ranks of households, using this score, were then used as a measure of SES. The association between SES and obesity (BMI ≥ 30) was assessed by means of chi-square tests and logistic regression. Results The overall prevalence of obesity at the AHDSS in the study period was 20.4%. Overall, sex -specific prevalences of obesity were 29.3% and 7.4% in females and males, respectively. Females aged 50-59 years and males aged 45-49 years had the highest age-specific prevalence of obesity, at 40.1% and 18.3%, respectively. The overall prevalence of central obesity was 31.1%. Sex-specific prevalence of central obesity in females was 51.1%, while in males it was 4.9%. The highest age-specific prevalence of central obesity in both sexes was for those 70 years and older: 74.3% in females and 11.1% in males. Around 50% of individuals at the AHDSS were classified as belonging to lower SES categories, with females constituting 56.6% of these individuals. The highest prevalence of individuals in the high SES category was females aged 60-69 (14.5%) and males aged 70 (16.4%) years and older. After adjusting for other variables, being in a lower SES category was inversely associated with obesity as measured by BMI, as was being male and being HIV positive. The only positive predictor of high BMI was older age. No association between central obesity and lower SES was found after adjusting for confounders and other explanatory variables. However, older age was a predictor of central obesity. Being male, HIV positive and the male head of the household were factors that were inversely associated with central obesity. Discussion The high prevalence of individuals in the lower SES group (50.5%) reported in this study is similar to the Mpumalanga provincial poverty estimate of 51%.The ratio of obese females to males was at least 2.2 in every age group. The prevalence of central obesity in females of 51.1% in the AHDSS was higher than the national estimate of 47.1% for females, while the male estimate of 4.9% was lower than the 6.8% national estimate for males. In contrast to other studies, no associations between lower SES and obesity as measured by central obesity were observed. Conclusion and Recommendations Specific interventions to reduce obesity in females should be undertaken, including the provision of educational talks. This would empower them to make better informed decisions about food and lifestyle choices. These recommendations should be integrated into already existing HIV prevention programmes because HIV prevention is currently the main focus of policy makers in South Africa. Measures to reduce the number of individuals in the lower SES group, which this study reported to be very high (especially among women), e.g. through job creation, should be considered.

A thesis submitted to the School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy June 2017 Johannesburg, South Africa / Non-communicable diseases (NCDs) pose an increasing burden on public health and economic growth worldwide. The highest increase in prevalence and death rates of NCDs has been seen in low and middle-income countries (LMICs). World Health Organization (WHO) estimates that by 2030, NCDs will account for five times as many deaths as communicable diseases in LMICs and that there will be more than 2.16 billion overweight and 1.12 billion obese individuals in the world. It is also estimated that by 2020 NCDs will contribute 80 percent of the global burden of disease and the largest increase in NCD deaths will occur in Africa. Recent reports indicate that six of the ten leading natural causes of death in South Africa are NCDs. There are few studies that have used longitudinal data to understand the effects of life-course childhood adiposity on future health risks and the early life factors responsible for variations in lifecourse childhood obesity. However, it is not known whether there is a genetic basis for the variability in BMI developmental patterns over time. Lack of comprehensive longitudinal and genetic association data for obesity have made it difficult to do such studies in an African setting. It is still not clear whether the same genetic variants associated with obesity in Europeans and other populations are also associated with these traits in African populations. Understanding the genetic contribution to obesity in the black South African population may help to come up with effective interventions to deal with this emerging epidemic in Africa. The aim of this thesis was to better understand the contribution of genetics and explain the longitudinal genetic basis of childhood and adolescence obesity in black South African children. To deal with this, I firstly studied identification of distinct trajectories of BMI and then relate the established BMI trajectories to the future health risks of elevated blood pressure. Secondly, I explored the early life factors behind BMI trajectory membership, this would help to identify factors that may accelerate an individual’s progression from a normal BMI trajectory pattern membership to the one characterized with elevated BMI. Then lastly, I looked at the additive genetic effect for BMI and determine whether genetic risk of obesity in early adulthood was mediated by early life rapid growth. Results showed variation in BMI developmental patterns between boys and girls; three and four distinct sex-specific BMI trajectories were identified in boys and girls respectively. Children belonging to early onset overweight or obese BMI trajectories, characterized by elevated BMI, had an increased risk of elevated blood pressure in late adolescence, compared to their peers in the normal trajectories. Rapid conditional relative weight gain in early life was associated with increased risk of belonging to a BMI trajectory characterized by consistent elevated BMI over time. Individuals in overweight or obese trajectories had a higher chance of being overweight or obese in early adulthood. I found that a genetic risk score, based on known adult BMI Caucasian risk variants, showed significant longitudinal effects of genetic loci with BMI in childhood and adolescent and significant age-GRS interactions were observed. A higher genetic risk score predicted membership of early onset obese or overweight BMI trajectories. The genetic risk of obesity at 18 years of age was mediated by pre-adolescence and adolescence rapid weight gain. The results from this thesis emphasize the importance of studying individual’s BMI developmental patterns when studying development and progression of obesity. These findings also show that the information obtained from GWAS done in other populations can be equally relevant to African populations and this could be used in early identification of individuals at increased risk of obesity and other NCDs risk factors. Combing genetic risk score, BMI trajectories membership and weight status can be used to help improve the screening process of individuals to be targeted in coming up with targeted educational and behavior intervention programmes for obesity. These programmes should target individuals at risk at early stage in order to reduce the adverse health risk outcomes later in life. / MT 2017

by Wong Wing Ki, Winnie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 47-55). / ABSTRACT --- p.ii / TABLE OF CONTENTS --- p.iii / LIST OF TABLES --- p.iv / LIST OF FIGURES --- p.v / CHAPTER / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 2 --- METHOD --- p.16 / Chapter 3 --- RESULTS --- p.23 / Chapter 4 --- DISCUSSION --- p.39 / REFERENCES --- p.47 / APPENDICES --- p.56

Obesity is a prevalent problem in modern society, which requires the upmost attention in the biomedical sciences. A leading cause of obesity related diseases is due to overeating, especially in industrialized countries. Leptin is the hormone that is secreted by fat cells responsible for communicating body nutritional status to the brain. Leptin interacts with other bodily systems such as the cognitive, digestive, neuronal, and endocrine systems. Leptin acts mainly on the Ob-Rb receptor in the arcuate nucleus of the hypothalamus and largely suppresses food intake and increases energy expenditure by activating Proopiomelanocortin and Cocaine- and amphetamine-regulated transcript (anorexigenic signals) neurons and by suppressing Neuropeptide Y and Agouti-related peptide (orexigenic signals) neurons, among other chemical signaling pathways. In both rodent and human studies, exogenous leptin administration resulted in elevated plasma leptin concentrations. When researchers tried to use leptin for weight reducing medical treatments in humans, the results show difficulty in establishing clinical efficacy. However, for diseases such as congenital leptin deficiency, obesity related leptin resistance, and lipodystrophy, medical treatments involving exogenous leptin have been relatively successful. The goal of this thesis is to give readers an understanding of leptin’s role in regulating appetite and the different leptin associated diseases. Leptin’s role is still continuing to be developed and more research is needed to fully utilize leptin for therapeutic benefit.

Background: Over the latter half of the last century, a dramatic increase in the prevalence of asthma has been observed. Over this same period there has been a substantial increase in the prevalence of obesity, this giving credence to the hypothesis that obesity and asthma may be causally associated. Aim: The main aims of this thesis were to: i) estimate the prevalence of asthma, allergic rhinitis, and atopic eczema in primary schoolchildren in Madinah, Saudi Arabia; ii) investigate the association between childhood obesity and prevalence of asthma; and iii) investigate possible mechanisms that might explain any associations observed. Methods: I undertook a pilot study aimed at testing the feasibility of conducting a large-scale descriptive epidemiological study of asthma and associated allergic disorders. This was followed by a two-stage cross-sectional survey, which was conducted to investigate the prevalence of asthma, allergic rhinitis, and atopic eczema in a sample of 5,188 schoolchildren, aged 6-8 years using an Arabic, validated version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Finally, I undertook an analytical study investigating the relationship between obesity and asthma. The cross-sectional study allowed for the identification of cases (i.e. those with a history of symptoms suggestive of asthma) and controls (i.e. those without a history suggestive of asthma). A sample of 632 cases and controls were recruited into a matched case-control study. Conditional logistic regression analysis, with appropriate adjustment for a range of potential confounders, was undertaken to explore the association between measures of obesity (in particular, body mass index (BMI)) and asthma. The possible aetiological roles of atopy and airway obstruction were studied by investigating the impact of sensitisation to common aeroallergens and measurements of lung function on the association between body mass index (BMI) and asthma. Results: In the pilot study, I found that the asthma, allergic rhinitis, and atopic eczema were very prevalent in children in Madinah and that further epidemiological studies were therefore likely to be feasible. The overall prevalence of children with a history of symptoms suggestive of asthma was 23.6% (95% CI: 21.3, 26.0); the prevalence among boys was estimated at 24.4% (95% CI: 22.0, 26.9) and among girls at 21.9% (95% CI: 17.4, 27.1), respectively. After adjustment for a number of possible confounders, BMI was found to be a significant predictor of the odds of asthma in both boys (OR=1.11; 95% CI: 1.03, 1.19) and girls (OR=1.38; 95% CI: 1.23, 1.56). When sensitisation to allergens was included in the analyses, the effect of BMI on the risk of asthma was no longer evident in boys (OR=1.09, 95% CI: 0.99-1.19) or girls (OR=1.25; 95% CI: 0.96-1.60). When the effect of lung function measures were factored into the model, the association however persisted: boys: OR=1.10 (95% CI: 1.02, 1.18) and girls OR=1.37 (95% CI: 1.22, 1.54). Conclusions: Asthma and related allergic disorders are very common in primary schoolchildren in Saudi Arabia. BMI is associated with symptoms suggestive of asthma in primary schoolchildren. This effect does not appear to be mediated through respiratory obstruction, but may, at least in part, be mediated through increasing the risk of allergic sensitisation. Prospective and more detailed gender-specific mechanistic studies are now needed to further investigate this association.

A reduction in the sensitivity of tissue to insulin is termed insulin resistance. In the clinic this condition is associated with obesity and inactivity and often leads to the development of type 2 diabetes. A major focus of antidiabetic therapy is to develop novel interventions to alleviate insulin resistance. However, the initial physiological and molecular defects in the development of insulin resistance remain elusive. This knowledge would greatly aid the development of novel and more effective insulin sensitisers.In an effort to improve the understanding of insulin resistance this thesis establishes that culturing liver cells in sera from obese diabetic patients reduces the ability of insulin to repress the key gluconeogenic gene, phosphoenolpyruvatecarboxykinase (PEPCK). Cells cultured in serum from obese diabetic human subjects exhibited defective PEPCK mRNA suppression by 0.1 and 0.5 nM insulin compared to cells cultured in control serum (p<0.0001), representing a shift to the right of the insulin dose response curve. Classification of human sera, using the response of the cell model following incubation with the sera, was actually more reliable than any single clinical biomarker at establishing whether the serum came from a volunteer with insulin resistance. This suggests that the cell model could be developed as a means to classify insulin resistance in the human population more reliably than simply measuring fasting glucose.The system was developed and optimised as a cell based humanised model of insulin resistance to aid the search for a biomarker for the development of obesity related insulin resistance. However, there was no linear relationship between any single biomarker and the resistance causing ability of the sera. Interestingly, cells cultured chronically in the presence of fetal calf serum supplemented with 5 pM insulin (the average increase in insulin between cases and controls) also exhibited reduced suppression of PEPCK by 0.1 and 0.5 nM insulin compared to controls (p=0.03 and 0.01 respectively). This has major implications for the understanding of how insulin resistance may develop. It suggests that minor increases in insulin release from beta cells, or minor loss of insulin clearance in the liver that elevate plasma insulin are potential initiating mechanisms for insulin resistance (at least in liver). Of course there may be many ways to initiate insulin resistance in vivo, but establishing the relative importance of the beta cell and the liver as an initial site for the development of insulin resistance is clearly important for effective intervention. Subsequent to the generation of insulin resistance in culture I could not detect significant differences in the response of the major post-receptor insulin signalling pathway components, between cells cultured under standard conditions and those cultured chronically in 5 pM insulin. Therefore the mechanism underlying this reduced insulin action on PEPCK gene transcription remains unclear.I then went on to develop reporter cell lines both for use in the study of the regulation of hepatic gene transcription by insulin and also as a potential screen for effective insulin sensitisers. Unfortunately the reporter cell lines did not turn out to be useful as hoped, as the reporter genes did not develop insulin resistance in response to chronic exposure to 5 pM insulin. In addition there were some differences between the reporter genes and endogenous genes in response to specific signalling inhibitors. This questions their suitability for the purposes proposed.Finally, I examined the signalling connections between the class of insulin sensitiser known as biguanides, and DNA repair mechanisms, as an initial characterisation of molecular links between diabetes and cancer. I established that inhibiting the DNA repair enzyme ATM reduces the phosphorylation of the biguanide target, AMPK in response to these drugs. However, although inhibition of ATM reduced biguanide suppression of G6Pase it had little effect on the regulation of PEPCK gene transcription by the drugs. This is consistent with AMPK not being the key mediator of biguanide regulation of PEPCK gene transcription and suggests that biguanide regulation of G6Pase and PEPCK gene transcription is mediated through distinct signalling pathways.In summary, I have developed a cell based model of insulin resistance that relies on factor (s) present in serum from humans with diabesity, and thus should be useful as a screen for more effective insulin sensitisers targeted at the population that donates the serum. It is likely that one of the factors responsible for generation of resistance is insulin itself as chronic exposure to low levels (albeit higher than background), of insulin reduces insulin sensitivity of the cells. The molecular details of the development of insulin resistance remain elusive as none of the major signalling pathways appear to be defective in the cells that have developed reduced insulin regulation of PEPCK. However, the data raise the intriguing possibility that chronic but mild hyperinsulinemia due to defective insulin secretion or clearance is an initial step in the development of insulin resistance. Hence, reducing insulin secretion (as opposed to current strategies of inducing insulin secretion) may be a more effective therapy for prevention of the development of insulin resistance. Finally, elements of the DNA repair pathways such as ATM may impinge on pathways that affect insulin sensitivity, including the biguanide target AMPK.