Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 203-231). Also available in print.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Objective: To evaluate the effect of exercise (EXE) alone or exercise combined with dietary supplements (EXE-SUPPL) on body composition and physical performance in subjects 60 years and older with sarcopenic obesity. Methods: A systematic review was carried out of studies identified through five search engines up to April 15, 2018. We searched for randomized controlled trials (RCTs) evaluating EXE or EXE-SUPPL in elderly individuals with sarcopenic obesity for at least six weeks. Primary outcomes were percentage of body fat mass, appendicular skeletal muscle mass, and hand grip strength. Random effects meta-analyses with the inverse variance method were used to evaluate the effects of interventions on outcomes. Effects were expressed as mean differences (MD) and their 95% confidence intervals (CI). Risk of bias was assessed with the Cochrane tool. Results: Nine papers reporting seven RCTs (with a total of 558 participants) were included in the review. EXE alone and EXE-SUPPL increased grip strength (MD 1.30 kg; 95% CI 0.58–2.01), gait speed (MD 0.05 m/s; 95% CI 0.03–0.07) and appendicular skeletal muscle mass (MD 0.40 kg; 95% CI 0.18–0.63). EXE alone and EXE-SUPPL reduced waist circumference (MD −1,40 cm; 95% CI −1.99 to −0.81), total fat mass (MD −1,77 kg; 95% CI −2.49 to −1.04), and trunk fat mass (MD −0.82 kg; 95% CI −1.22 to −0.42). Conclusion: EXE alone and EXE-SUPPL improved muscle-related outcomes and reduced fat-related outcomes in subjects with sarcopenic obesity. There is a need for better-designed RCTs with systematic assessment of both different exercise regimes and dietary supplements in sarcopenic obese subjects. / Revisión por pares

M.A.(Psychology) / The principal aim of the present study was the determination of the role of aggression, the self concept and stereotyping in obesity. A subsidiary goal was to construct a scale for the measurement of stereotyping. A scale for the measurement of the stereotyping of obese women was constructed and applied to a general sample of 229 first year psychology students. This scale, namely the Attitude Questionnaire (AQ), comprised forty 7-point scales. The first 20 scales were designed to characterise obese women and the last 20 scales to characterise normal weight women. Separate item analyses were done for the first and the second parts of the scale. The first part of the scale yielded a reliability coefficient of 0,86 according to Kuder-Richardson Formula 20 and the second part a coefficient of 0,87. The first part of the scale was subjected to a factor analysis to determine its structure. It yielded a single second-order factor which was defined as "general stereotyping of obese women". Similarly the second part of the AQ yielded a single second-order factor which was defined as "general stereotyping of normal weight women". The scores of the student sample, in respect of the AQ,were used in order to determine their perception of obese women compared with normal weight women. The vector of means of obese women were contrasted with the vector of means of normal weight women and the difference between the two vectors was tested with the aid of Hotelling T2 (dependent test). The Hotelling T2 proved to be statistically significant and was consequently followed up by a series of t-tests. From the t-tests it transpired that the perception of the student sample of obese women was largely negative. A battery of tests comprising the Picture Situation Test (PST), the Buss-Durkee Hostility Inventory, the Adolescent Self-Concept scale (ASCS) and the newly constructed AQ, was administered to 50 obese women who were members of the . Weight Watchers organisation (experimental group) and 50 Weight Watchers organisation (experimental group) and 50 normal weight women who worked for a large cosmetic company (control group)

Obesity, or the presence of an excessive amount of body fat is a major public health problem in the United States and, increasingly, the rest of the world. The apparent drivers of the increased prevalence of obesity over the past several decades are environmental changes, e.g., dietary and lifestyle changes that interact with the individual’s genetic susceptibility for weight gain. In humans, obesity appears to be driven primarily by increases of energy intake relative to expenditure; that is, to uncompensated hyperphagia. The heritability of adiposity, i.e., the extent to which differences in adiposity among individuals living in the same environment can be attributed to genetic differences is estimated by twin and other studies to be about 50%. Large scale population-based association studies (e.g., GWAS) have suggested that genetic variants (e.g., SNPs) associated with susceptibility or resistance to obesity affect primarily the development and regulation of the central nervous system (CNS). In particular, SNPs in genes that play a role in brain cellular structures and molecular pathways known to regulate energy homeostasis, most notably, the leptin-melanocortin signaling pathway, are among the most highly associated with human obesity. For example, SNPs around the melanocortin receptor, MC4R, are associated with increased adiposity and mutations in MC4R represent the most prevalent genetic variations associated with monogenic obesity. Ultimately, however, relatively little is understood about the biological mechanisms by which an individual’s genetic sequence confers susceptibility or resistance to weight gain in a specific environment. Such understanding could open new avenues for the prevention and treatment of obesity and would advance our understating of genetic predisposition to other complex diseases. The goal of this research is to identify genomic regions contributing to susceptibility and resistance to hyperphagic obesity by analysis of whole genome sequence and hypothalamic gene expression data from two genetically related cohorts of Sprague-Dawley rats – the ‘Levin Rat’. Dr. Levin developed these animals by successive generations of selective breeding for differences in adiposity resulting from exposure to a calorically dense, highly palatable diet (described in detail in Chapter 2). These selectively bred diet-induced obese (DIO) and diet-resistant (DR) Levin rats have been the topic of a large body of physiological research (reviewed in Chapter 1) showing potentially important similarities to the physiology of human obesity. In particular, implication of diet-sensitive hyperphagia as the primary driver for the differential susceptibility of DIO (diet-induced obese) animals to gain weight in response to palatable diet; neuroanatomical and functional differences between DIO and DR in hypothalamic nuclei (e.g., ARH, PVH) and leptin signaling, prior to the development of obesity; and, neurophysiological differences between DIO and DR (diet-resistant) in ‘reward circuit’ nuclei (e.g., NAc) and their differential responses to pharmacological stimuli, e.g., cocaine, as well as palatable diet. These findings established the Levin rat as an interesting model for aspects of the biology of human obesity. Importantly, the genetic bases for these Levin rat phenotypes have remained unknown. Our efforts to elucidate the underlying genetics of this model system are, therefore, of potential relevance to human obesity. We obtained phenotypic, whole genome sequence (WGS) and hypothalamic gene expression (RNA-Seq) data from selected Levin rats and analyzed these data to identify several loci that are highly associated with the body weight phenotype in the Levin cohorts, as well as in a confirmation cohort of genetically related progeny being studied for phenotypes related to addictive behaviors. In Chapter 2, I describe our methods and approaches to collecting the relevant phenotypic and genetic data, and to selecting primary and confirmation cohorts for the WGS and RNA-Seq studies. In Chapter 3, I describe our bioanalytical and statistical approaches to the WGS data designed to detect genomic loci likely inherited Identical by Descent (IBD) from common ancestors of the DIO, or DR animals; such loci constitute candidate obesity susceptibility loci for the Levin rat. In Chapter 4, I present the phenotypic differences between the DIO and DR animals used for the study, the results of IBD analysis of the WGS, and indicate genes we found to be differentially expressed or spliced in their respective hypothalami. I also show, using confirmation groups (CG) of animals from the primary cohorts of Levin rats (not used for IBD mapping), that the identified susceptibility loci are highly associated with DIO/DR lineage. In Chapter 5 I show, using representative SNPs from the loci with the highest association to the obesity susceptibility phenotype, significant association between the ‘DIO’ genotype and increased body weight in an independent cohort of Levin rat progeny [designated Obesity Prone (OP) and Obesity Resistant (OR)] maintained by Dr. Ferrario (U. Michigan). Using gene set enrichment analyses (GSEA), I show that the candidate susceptibility loci are enriched in CNS genes and genes previously associated with obesity traits in human GWAS. I also analyzed the genes implicated by differential expression and/or splicing (RNA-Seq) in relation to the genetic susceptibility map (IBD analyses) and identified several genes whose hypothalamic differential regulation (e.g., expression, splicing) may be linked to genetic sequence variations between the DIO and DR animals. Interestingly, essentially, all of the identified genes have been previously implicated in body weight regulation in other species, including humans. Finally, I propose future studies to build upon this work in order to further refine the genetic susceptibility map, test the roles of putative candidate genes, and ultimately elucidate the genetic bases for the differences in body weight in this genetically complex mammalian model of diet-sensitive obesity: the Levin DIO/DR rats. In summary, the conclusions from these studies are that: - The 15 susceptibility loci we identified, span in total ~35 Mb, or 1.15% of the rat genome, likely contain a significant portion of the causal alleles underlying the Levin rat phenotype. - The majority of genetic variants in these susceptibility loci are ‘non-coding,’ e.g., intronic, in untranslated regions, or intergenic – similar to common obesity SNPs. - Our susceptibility map is enriched for genes governing CNS function and development, and its human syntenic genes/loci are enriched in obesity SNPs, identified by GWAS. Therefore, Levin rat obesity risk may have a genetic architecture similar to that in humans. - We identified several genes that are differentially expressed or spliced in the hypothalamus of DIO/DR animals, and are also implicated by our genetic map: Zfr, Slc24a2, Fhit, Adarb1, Lrp2. Interestingly, human orthologs of all of these genes have been implicated in obesity by GWAS or familial linkage studies, enhancing them as putative candidates for a role in the Levin rat obesity phenotypes. - Our studies further establish the Levin rat as a model system for polygenic human obesity and lay the foundation for further studies to elucidate the genetic basis of this interesting and important complex trait of hyperphagic diet-sensitive obesity.

Implementation of an Evidence-Based Childhood Obesity Toolkit in a Rural Pediatric Clinic in Cookeville, TN: A Quality Improvement Project Dawn G. Johnson, MSN, APRN, FNP-BC Tennessee Technological University Nursing 6802 – DNP Project Development Dr. Victoria Pope & Dr. Candice Short March 23, 2022 Author Note Dawn G. Johnson https://orcid.org/0000-0002-7090-8036 College of Nursing, Tennessee Technological University There are no conflicts of interest to disclose. Correspondence concerning this manuscript should be addressed to Dawn G. Johnson, Tennessee Technological University, 248 Haven Lane, Algood, TN 38506 Email: djohnson@tntech.edu Abstract Purpose: The purpose of this quality improvement project is to increase the early identification of overweight or obese children in the primary care setting and provide education through the implementation of an evidence-based childhood obesity toolkit. Aims: This project aims to implement the Healthy Care for Healthy Kids Physical Activity and Nutrition Survey Management Plan to educate patients and parents about childhood obesity. The Healthy Care for Healthy Kids Physical Activity and Nutrition Survey Management Plan is an evidence-based questionnaire and action plan used by healthcare providers in the prevention and treatment of childhood obesity. Processes: Nurses will provide the toolkit to children ages 5-18 who present to the clinic for well-child examinations and have a BMI classified as overweight or obese. Providers will then review the screening toolkit with the patient and family and make a corrective plan of action. The screening tool will then be signed by the patient, caregiver, and provider and placed in the child’s electronic medical record. Results: To be determined after project implementation is complete. Results are anticipated to be that more overweight and obese children are identified by the clinic and proper education is provided to the patient and family. Limitations: The study is limited to one location and only available to the providers who perform well-child examinations. Conclusions: Implementation of an evidence-based childhood obesity toolkit in the pediatric setting with increase the early identification of overweight and obese children. Keywords: childhood obesity, pediatric obesity, toolkit, obesity, overweight

Yes / Obesity research priority setting, if conducted to a high standard, can help promote policy-relevant and efficient research. Therefore, there is a need to identify existing research priority setting studies conducted in the topic area of obesity and to determine the extent to which they followed good practice principles for research priority setting. Studies examining research priority setting in obesity were identified through searching the MEDLINE, PBSC, CINAHL, PsycINFO databases and the grey literature. The nine common themes of good practice in research priority setting were used as a methodological framework to evaluate the processes of the included studies. These were context, use of a comprehensive approach, inclusiveness, information gathering, planning for implementation, criteria, methods for deciding on priorities, evaluation and transparency. Thirteen articles reporting research prioritisation exercises conducted in different areas of obesity research were included. All studies reported engaging with various stakeholders such as policy makers, researchers and healthcare professionals. Public involvement was included in six studies. Methods of research prioritisation commonly included both Delphi and nominal group techniques and surveys. None of the 13 studies fulfilled all nine of the good practice criteria for research priority setting, with the most common limitations including not using a comprehensive approach and lack of inclusivity and evaluating on their processes. There is a need for research priority setting studies in obesity to involve the public and to evaluate their exercises to ensure they are of high quality. / National Institute for Health Research (NIHR) under its Applied Research Collaboration (ARC) Yorkshire and Humber in the form of Ph.D. funding to HI [NIHR200166], the UK Prevention Research Partnership (UKPRP) in the form of funding to JW and RM [MR/S037527/1], the NIHR Clinical Research Network in the form of funding to JW, and the NIHR ARC Yorkshire and Humber in the form of funding to RM

This study takes the form of exploratory and descriptive research in which children in middle childhoods’ experience of their obesity was explored and described. A case study research design was used in a qualitative approach and data was gathered through semi-structured interviews. The data analysis spiral of Cresswell was implemented in order to facilitate the research process. Empirical findings present the experiences obese children in middle childhood undergo with regard to different areas of their development. The researcher drew upon literature relating to obesity and middle childhood development in order to analyse and verify collected data in pursuit of describing children’s experience of their obesity. Emotional hideaway amongst obese children, the role of the family in an obese child’s life and the reason why obese children make the wrong food choices are some of the topics not addressed in the limited scope of this project. The possibility of exploring these final thoughts provides opportunity for future research. / Social Work / M.Diac. (Play Therapy)

Maternal obesity is an increasing concern in the obstetric population. It confers increased morbidity and mortality to the mother and offspring during pregnancy and delivery as well as potential long-term increase in risk of ill health to the offspring. There are currently few effective interventions and no pharmacological therapies. Potential mechanisms to account for ill health in obese non-pregnant individuals include excess inflammation, both systemically and within specific tissues such as adipose, as well as alterations in metabolic regulation including hyperglycaemia, reduced sensitivity to insulin and altered adipokine expression. In healthy pregnancy, there are significant adaptations to maternal metabolism, including the development of profound systemic insulin resistance. We hypothesize that there exists an interaction between the metabolic adaptations of pregnancy and those occurring in obesity which could provide a physiologically plausible mechanism which could contribute to the pathogenesis of adverse outcomes associated with obese pregnancies. In this thesis, we sought to understand and define the metabolic adaptations to pregnancy in severely obese women. Anthropometric characteristics are described in a longitudinal case-control study of apparently healthy obese (BMI > 40kg/m2) pregnant women. Systemic adipokine and pro- inflammatory cytokine profiles were measuring using ELISA. Indices of insulin sensitivity were assessed at three time points in pregnancy. In a cohort study of healthy pregnant women in the third trimester, transcript levels of adipokines and inflammatory cytokines in paired subcutaneous and omental adipose tissue biopsies were quantified and correlated these transcript levels with booking body mass index (BMI). Obese pregnant women gained less weight in pregnancy compared to lean women, but had significantly elevated fasting third trimester glucose, as well as elevated blood pressure and fasting insulin resistance throughout pregnancy. Fasting leptin was elevated throughout pregnancy in obese compared with lean pregnancy women; however, in the third trimester there was no correlation between adipose tissue leptin mRNA levels and BMI. Transcript levels of IL-6 were positively correlated with BMI in subcutaneous but not omental adipose tissue; no other positive correlations with BMI were shown. Hyperinsulinaemic euglycaemic clamps with concomitant use of stable isotope tracers were carried out in a case-control study of healthy obese pregnant women to characterise in detail whole body insulin sensitivity, endogenous glucose production and rate of lipolysis. In contrast to the original hypothesis, by the third trimester, there were few differences between lean and obese pregnant women in whole body glucose disposal (WGD) and endogenous glucose production. Compared with non-pregnant women, lean pregnant women demonstrated approximately 60% decrement in WGD; in contrast, obese non-pregnant women were already significantly insulin resistant but did not develop further insulin resistance in response to pregnancy. 3-Tesla (3T) Magnetic Resonance Imaging (MRI) and 1H-Magnetic Resonance Spectroscopy (1H-MRS)was used to assess abdominal fat distribution, hepatic and skeletal muscle lipid content in a case-control study of healthy pregnant women in the third trimester. As expected, obese pregnant women have greater adipose accumulation in both subcutaneous and intra-abdominal adipose depots and greater lipid accumulation in skeletal muscle. However, hepatic lipid content was low in both groups and there were no significant differences between lean and obese pregnant women. This was not expected as both groups are profoundly insulin resistant at this at this gestation, and in non-pregnant individuals, insulin resistance at this level would be expected to drive hepatic lipid accumulation, and may point to a pregnancyspecific hepato-protective mechanism. In conclusion, in this thesis, it has been shown that while obese women are insulin resistant with an adverse metabolic profile, that there does not appear to be the expected worsening of this profile in response to pregnancy and that by the end of pregnancy, lean women have a similar phenotype. Instead, while lean women are exposed to this environment only towards the end of pregnancy, obese women and their offspring are exposed throughout gestation, including key periods of fetal development in early pregnancy. This prolonged exposure may account for the excess pathologies in such pregnancies, potentially by exhausting what physiological reserve such women have pre-pregnancy. Potential therapies must therefore be optimally timed to improve the metabolic profile of obese women in early pregnancy, without hindering the required adaptations of the third trimester.

BACKGROUND: Little is known about preschool parents' cognitions, barriers, supports and modeling of key obesogenic behaviors, including breakfast, fruit and vegetable consumption, sugary beverage intake, feeding practices, portion sizes, active playtime, reduced screen-time, sleep and selection of child-care centers with characteristics that promote healthy behaviors. METHODS: Thus, the purpose of this study was to examine these factors via survey and focus groups among 139 parents of 2- to 5-year-old children. Standard content analysis procedures were used to identify trends and themes in the focus group data, and Analysis of Variance was used to test for differences between groups in the survey data. RESULTS: Results showed 80% of parents ate breakfast daily, consumed sugary beverages 2.7 ± 2.5SD days per week, and had at least two different vegetables and fruits an average of 5.2 ± 1.8SD and 4.6 ± 2.0SD days per week. Older parents and those with greater education drank significantly fewer sugary drinks. Parents played actively a mean 4.2 ± 2.2 hours/week with their preschoolers, who watched television a mean 2.4 ± 1.7 hours/day. Many parents reported having a bedtime routine for their preschooler and choosing childcare centers that replaced screen-time with active play and nutrition education. Common barriers to choosing healthful behaviors included lack of time; neighborhood safety; limited knowledge of portion size, cooking methods, and ways to prepare healthy foods or play active indoor games; the perceived cost of healthy options, and family members who were picky eaters. Supports for performing healthful behaviors included planning ahead, introducing new foods and behaviors often and in tandem with existing preferred foods and behaviors, and learning strategies from other parents. CONCLUSIONS: Future education programs with preschool parents should emphasize supports and encourage parents to share helpful strategies with each other.

Obesity is associated with an increased risk of diabetes type 2, dyslipidaemia and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by dietary fats such as cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are also implicated in the pathogenesis of obesity, metabolic syndrome and atherosclerosis. Transgenic mice over-expressing 11β-HSD1 selectively in adipose tissue develop the metabolic syndrome whereas 11β-HSD1-/- mice have a ‘cardioprotective’ phenotype, deriving in part from improved adipose tissue function. Consistent with this, prototypical therapeutic 11β-HSD1 inhibitors ameliorate metabolic disturbances associated with obesity. 11β-HSD1 also inter-converts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-HC). Work presented in the first part of the thesis defines the impact of these alternative substrates on the metabolism of glucocorticoids in adipocyte cell lines (3T3-L1 and 3T3-F442A). 11β-HSD1 catalyses the reduction of 7KC in mature adipocytes leading to accumulation of 7β-HC. Oxysterol and glucocorticoid conversion by 11β-HSD1 was competitive and occurred within a physiologically-relevant IC50 range of 450nM for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11β-HSD1 activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of preadipocyte differentiation. 7-oxysterols did not display intrinsic activation of the glucocorticoid receptor (GR). However, when co-incubated with glucocorticoid, 7KC repressed, and 7β-HC enhanced GR transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11β-HSD1 reaction direction, at least in transfected HEK293 cells, and could be abrogated by over-expression of hexose 6-phosphate dehydrogenase, which supplies NADPH to drive the reductase activity of 11β-HSD1. 11β-HSD1 inhibition protects from atherosclerosis, yet it is unknown whether it is an effect of alterations in the metabolism of 7-oxysterols. 7KC and 7β-HC did not activate the potential cognate receptor LXRα and FXR/RXR in transactivation assays. No differential regulation of key gene targets of LXRα, FXR and RORα in the liver and fat depots of high fat fed 11β-HSD1-/- and wild type mice was observed. To further determine the molecular basis for the metabolically beneficial phenotype of 11β-HSD1-/- mice I analysed global gene expression in subcutaneous and mesenteric adipose tissues of high fat-fed (4 weeks) 11β-HSD1-/- and congenic C57BL/6J mice by microarrays, followed by pathway analysis, gene clustering and realtime-PCR validation of transcripts with >1.5-fold difference between genotypes. 11β-HSD1-/- mice gained less weight and distributed adipose tissue to subcutaneous rather than visceral depots. Broadly, high fat-fed 11β-HSD1-/- mice showed up-regulation of transcripts in subcutaneous fat (70% of 1622 differentially-expressed transcripts), but down-regulation in mesenteric adipose tissue (73% of 849 transcripts). Genes up-regulated in 11β-HSD1-/- subcutaneous adipose were associated with β-adrenergic signaling, glucose metabolism, lipid oxidation, oxidative phosphorylation, MAPK, Wnt/β-catenin, EGF, and PI3K/AKT insulin signaling pathways. Increased subcutaneous fat insulin signaling was confirmed by increased IRS-1 and Akt phosphorylation in vivo. Down-regulated genes in 11β-HSD1-/- mesenteric fat were associated with immune cells, NK-kappaB, Jak/Stat, SAPK/JNK, chemokine, toll-like-receptor and Wnt signaling pathways suggesting reduced immune cell infiltration in mesenteric adipose in high fat-fed 11β-HSD1-/- mice. 11β-HSD1 deficiency protects against metabolic disease by increasing peripheral fat insulin sensitivity and through a novel mechanism involving reduction in visceral fat immune/inflammatory cell function. Data presented in this thesis contribute to the understanding of the role of 11β-HSD1 in adipose tissues in obesity and, potentially, atherosclerosis.