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BARBACINI, PIETRO. "IMPACT OF VITAMIN D DEFICIENCY, DYSLIPIDEMIA AND OBESITY ON SERUM LIPIDOMIC PROFILE. SEARCH FOR NEW BIOMARKERS AS EARLY PREDICTORS OF OBESITY-ASSOCIATED COMORBIDITIES." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/710504.
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Research studies indicate that up to 58% of the world adult population will be overweight or obese by 2030 [1]. Obesity is not only related to food intake, but factors such as lifestyle and genetic background contribute to its onset [3–5]. This disease [2] is commonly associated with vitamin D (Vit. D) deficiency [6,7], and genetic associations have been identified to explain this link [8]; however, differences in dietary intake, sun exposure, or Vit. D metabolism are also involved [9]. Moreover, along with Vit. D deficiency, lipids, and particularly sphingolipids (SLs) as ceramides (Cers) and sphingomyelins (SMs) have been described as involved, not only in increasing inflammation [10,11], but also in the development of cardiovascular disease and type two diabetes [12–14], two common conditions observed in obese subjects. Given the pivotal role of SLs in obesity associated co-morbidities and the association of Vit. D, dyslipidemia and obesity, our study was aimed at profiling circulating SLs in human subjects under these conditions, in order to provide hints for the identification of new biomarkers to be introduced in clinical settings.
To define human SLs profile in obesity, dyslipidemia, and Vit. D associated deficiency, sera from 23 normal-weight normolipidemic (NWNL), 46 normal-weight, dyslipidemic, Vit. D deficient (NWDL) and 60 obese dyslipidemic, Vit. D deficient (ODL) Saudi Arabian subjects were analyzed with a dual approach, characterized by the use of two complementary techniques: the HPTLC-Primuline profiling and the LC-MS analysis. Furthermore, to define SLs profiles in the context of human adaptation to high altitude hypoxia, sera from 59 Vit. D deficient dyslipidemic children living at high altitude were analyzed by LC-MS. Children were grouped based on their BMI percentiles in 7 underweight (UW), 30 normal-weight (NW), 13 overweight (OW) and 9 obese (O).
SLs profile analysis of NWNL and ODL Saudi Arabian subjects displayed differences in total Cer and total SM caused by dyslipidemia and vitamin D deficiency, whereas specific Cers, and SMs acyl chains characterize obese subjects, only. Gender differences were found in SLs profiles independently from dyslipidemia and Vit. D status. Obesity-associated Cers, SMs, and dihydrosphingomyelins (dhSMs) specific acyl chains were identified in the NWDL vs. ODL comparison independently from dyslipidemia and Vit D status, and are thought to be drivers of increased risk of developing obesity-associated morbidities.
The analysis of SLs profiles from dyslipidemic children with Vit. D deficiency allowed to confirm the results of Saudi Arabian subjects regarding SLs association with dyslipidemia and associated Vit. D deficiency. Furthermore, SLs profile analysis led to the identification of a characteristic SLs portraits associated with BMI and related to hypoxia metabolic adaptation.
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Sukkar, Louisa. "Improving outcomes in chronic kidney disease and its associated comorbidities." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25667.
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Background: Chronic kidney disease (CKD) and its associated comorbidities such as diabetes and cardiovascular disease (CVD) are major drivers of death and disability around the world. Methods: This thesis by publication aims to examine the burden of CKD and diabetes in the community and explores the ways in which this burden can be ameliorated. These aims are achieved by various methodologies. A novel comprehensive population-based data linkage study is used to estimate CKD and diabetes incidence and associations as well as assesses health service delivery of proven cardioprotective treatments to mitigate the burden of CVD. An observational extension of a randomised controlled trial (RCT) cohort of people with CKD is used to investigate the legacy effect of statins on CVD. A narrative review examines the RCT evidence for the CV and kidney protection of novel glucose lowering agents for the treatment of diabetes. Systematic review and meta-analyses are used to examine treatment options to mitigate the effect of Acute kidney injury (AKI) a precursor of CKD.
Results: This research program has demonstrated the high burden of CKD and diabetes in the community and identified risk factors that can be targeted to inform health service planning and resource allocation. New data is presented that demonstrates the significant missed opportunities in the use of cardioprotective therapies for CVD prevention. A literature review of glucose lowering agents showed CV and renal protection in people with and without pre-existing CVD. A systematic review of two currently used treatments for the management and prevention of AKI found no evidence for their continued use. Conclusions: Collectively the findings of this thesis have the potential to inform the design of strategies to target and readily implement solutions to improve health outcomes in CKD and diabetes.
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Mele, Chiara. "Multifold aspects of obesity and insulin resistance: comorbidities and crosstalk with thyroid gland." Doctoral thesis, Università del Piemonte Orientale, 2018. http://hdl.handle.net/11579/102829.
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Jackson, L. "Psychological factors associated with obesity." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/14241/.
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Barroso, Joana Barbara de Bessa. ""Obesity and inflammation: associated polymorphisms"." Master's thesis, Faculdade de Medicina da Universidade do Porto, 2008. http://hdl.handle.net/10216/23729.
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Barroso, Joana Barbara de Bessa. ""Obesity and inflammation: associated polymorphisms"." Dissertação, Faculdade de Medicina da Universidade do Porto, 2008. http://hdl.handle.net/10216/23729.
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McNamara, Renae J. "Effect of water-based exercise in people with COPD with physical comorbidities." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13271.
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People with chronic obstructive pulmonary disease (COPD) and physical comorbidities such as obesity, musculoskeletal, orthopaedic and neurological conditions have reduced free-living daily physical activity compared to people with COPD and healthy age-matched individuals. Less time is spent in light and moderate intensity physical activity and greater time is spent in sedentary behaviours. Water-based exercise training (WBET) may be an alternative to traditional land-based exercise training (LBET) for people with COPD and physical comorbidities (COPD+PC). Previous studies have shown positive outcomes for exercise capacity and quality of life following WBET, however these results were inconclusive given the trials were low in quality. In a prospective randomised controlled trial comparing an eight-week supervised WBET program to an equivalent eight-week supervised LBET program and a control group of no exercise training, WBET was found to be significantly more effective than LBET and no exercise training in increasing peak and endurance exercise capacity and improving aspects of quality of life in people with COPD+PC. In addition, obese participants randomised to the WBET program lost a greater amount of weight over the eight-week training period than participants in the LBET and no exercise training groups. WBET was found to be well accepted by people with COPD+PC, with no adverse events occurring during the training period. Furthermore, high satisfaction with the aquatic environment was reported. In a Cochrane review examining the effect of WBET in people with COPD, WBET was found to significantly improve exercise capacity (functional, peak and endurance exercise capacity) and quality of life compared to no exercise training. Compared to LBET, WBET was found to significantly improve endurance exercise capacity and fatigue. Limited quality evidence exists that WBET in people with COPD is safe and effective.
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Blaszczak, Alecia Marie. "Defining the Inflammatory Microenvironment of Human Adipose Tissue in Obesity and How It Contributes to the Development of Obesity-Related Comorbidities." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1553601004244596.
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Van, Guilder Gary Preston. "Vascular endothelial abnormalities associated with obesity." Diss., Connect to online resource, 2006. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3219223.
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Rizzolli, Jacqueline. "Obesidade grau III : considerações sobre complicações clínicas e tratamento cirúrgico." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2005. http://hdl.handle.net/10183/8411.
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A obesidade grau III ou também chamada obesidade mórbida é uma condição clínica freqüente e que vem apresentado crescimento progressivo, estando associada a elevadas taxas de morbi-mortalidade. Trata-se de uma doença de origem multifatorial, freqüentemente associada a comorbidezes, necessitando uma abordagem terapêutica que propicie redução de peso, melhora das doenças associadas e conseqüente melhora da qualidade de vida. O tratamento convencional deve ser sempre a primeira escolha, principalmente nos casos de inicio recente e sem antecedentes de tratamentos adequados prévios. A taxa de insucesso, contudo, é extremamente elevada, ocorrendo falha em mais de 90% dos casos. O tratamento cirúrgico atualmente é a alternativa com melhores resultados, porém com riscos de complicações a curto, médio e longo prazo, caso não seja realizado um rigoroso acompanhamento clinico, nutricional e psicológico em equipe multidisciplinar experiente. Esta revisão tem por objetivo discorrer sobre as morbidades associadas à obesidade grave, as opções de tratamento convencional e cirúrgico bem como riscos relacionados à persistência de um grande excesso de peso versus risco cirúrgico.<br>Morbid obesity is a frequent disease with a progressive increase in incidence and associated with high morbid and mortality rates. It is a multifactorial disease, and is usually associated with comorbidities. It is necessary specific treatment to reduce weight, to improve the comorbidities and obtain a better quality of life. The classic treatment, diet and exercise, should be the first choice, especially in cases of recent onset of severe obesity and poor quality previous treatments. Unfortunately, in more than 90% of the patients this kind of treatment will fail. Bariatric surgery is, nowadays, the best option of treatment, but has several risks of complications in the short, medium or long time followup, mostly in patients not followed by a specialized multidisciplinary team. This is a review about morbid obesity, comorbidities, options of treatment and the risks of stay severely obese versus surgical procedures.
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Ryan, K. E. "Reduction of cardiovascular risk associated with obesity." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411802.
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Banting, Esme. "Investigating the psychological factors associated with obesity." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:ac7e230e-a4ec-40c6-a34f-045ee6693b89.
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Obesity is one of the most serious public health challenges of the 21<sup>st</sup> century, associated with a range of adverse physical, psychological, social and economic consequences. The aetiology of obesity is complex; however, the psychological factors associated with overweight and obesity remain poorly understood. The first paper critically appraises evidence for three of the most developed psychological theories of obesity. Based on these findings, literature from the fields of emotion regulation and attachment are reviewed, and a novel developmental theory of obesity based on an integration of these theoretical constructs is proposed. Recommendations for future research based on a theoretical framework of emotion regulation are made, and implications for clinical practice including a focus on enhancing caregiver sensitivity are highlighted. The second paper explores the applicability of an established cognitive model of Bulimia Nervosa (BN) and binge eating to an overweight and obese sample. Findings support the relevance of cognitive aspects of the model in an overweight and obese sample, and highlight the potential role of early attachment relationships in the formation of cognitions that make an individual vulnerable to overweight and obesity in later life. Theoretical and clinical implications based on the established cognitive model are considered. Limitations include reliance on self-report and the correlational nature of analyses used. Recommendations for future research with larger, more representative samples to address these limitations are made. Overall, this dissertation makes a unique contribution to the psychological understanding of overweight and obesity, which has the potential to enhance treatment outcomes and suggests useful avenues for further research.
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Manuel, Ari. "Factors associated with ventilatory failure in obesity." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:6e02399d-14d3-4601-9e63-0d1e446a2c3c.
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Introduction: Only a third of obese patients develop chronic ventilatory failure. This cross-sectional study assessed multiple factors potentially associated with chronic ventilatory failure. Materials/Patients and Methods: Participants had a body mass index (BMI) > 30 kg/m(2), with or without chronic ventilatory failure (awake arterial partial pressure of carbon dioxide > 6 kPa or base excess (BE) =2 mmols/L). Factors investigated were grouped into domains: (1) obesity measures, (2) pulmonary function, (3) respiratory and non-respiratory muscle strength, (4) sleep study derivatives, (5) hypoxic and hypercapnic responses, and (6) some hormonal, nutritional and inflammatory measures. Results: 71 obese participants (52% male) were studied over 27 months, 52 (SD 9) years and BMI 47 (range 32-74) kg/m(2). The best univariate correlates of BE from each domain were: (1) dual-energy X-ray absorptiometry measurement of visceral fat (r=+0.50, p=0.001); (2) supine forced expiratory volume in 1 s (r=-0.40, p=0.001); (3) sniff maximum pressure (r=-0.28, p=0.02); (4) mean overnight arterial oxygen saturation (r=-0.50, p < 0.001); (5) ventilatory response to 15% O2 breathing (r=-0.28, p=0.02); and (6) vitamin D (r=-0.30, p=0.01). In multivariate analysis, only visceral fat and ventilatory response to hypoxia remained significant. Conclusions: We have confirmed that in the obese, BMI is a poor correlate of chronic ventilatory failure, and the best independent correlates are visceral fat and hypoxic ventilatory response.
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Pritchett, Lanae, Jennifer Knutson, and Grant Skrepnek. "Comorbidities Associated with Polycythemia Vera and Factors Influencing Cost and Mortality in Inpatient Hospital Settings." The University of Arizona, 2011. http://hdl.handle.net/10150/614608.
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Class of 2011 Abstract<br>OBJECTIVES: To assess the role of patient, payer, clinical and disease-related factors in charges and mortality among adult inpatient cases of polycythemia vera in the United States from 2004 to 2008.
METHODS: This retrospective cohort study utilized hospital discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) five consecutive years from 2004 to 2008.
RESULTS: There were a total of 156,490 episodes of care involving polycythemia vera between 2004 and 2008. Average age upon admission was 65.94 years (±16.03), with 56% of cases being male (n=87,662). The mean length of stay was 5.14 days (±5.31) and inpatient mortality occurred in 3.1% of cases (n=4,927). The mean number of procedures performed was 1.43 (±2.08) and the mean number of diagnoses on record was 9.56 (±3.86). Charges for each episode of care averaged $32,620 (±42,801), summing to a national bill of $5.02 billion (2010 dollars) over the five-year time horizon. Higher charges were associated with longer length of stay, larger hospital bed size, urban hospital location, teaching status, increased number of diagnoses and procedures, private payer, Western U.S. region, and higher income bracket. Increased mortality was associated with increased age, increased number of diagnoses and procedures, self pay, payer other than Medicare, Medicaid, private or self, and the comorbidities of congestive heart failure, coagulopathy, and fluid/electrolyte disorders.
CONCLUSION: Polycythemia vera is associated with considerable burden of illness.
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Dong, Feng. "Role of leptin in obesity-associated cardiac dysfunction." Laramie, Wyo. : University of Wyoming, 2006. http://proquest.umi.com/pqdweb?did=1273128981&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Abu-Rmeileh, Niveen Mohammad Elias. "Familial and non-familial factors associated with obesity." Thesis, University of Glasgow, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439221.
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Gibeon, David. "The role of adipokines in obesity-associated asthma." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/44500.
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Obesity is a risk factor for the development of asthma and plays a role in disease control, severity and airway inflammation. The relationship between asthma and adiposity is multifactorial and incorporates in-utero conditions, genetic factors, comorbidities and inflammation secondary to excess adipose tissue. Adipocytes produce cytokines, termed adipokines, which play an important role in systemic inflammation and have been correlated to the development of asthma and disease severity. Retrospective analysis of trials using inhaled corticosteroids and an in vitro study using alveolar macrophages has associated obesity with corticosteroid insensitivity in asthma. The first part of this study looked at data taken from a large cohort of well-characterised severe asthmatics and compared patient demographics, disease characteristics, healthcare utilisation and medication according to body mass index (BMI). Lipid laden macrophages (LLMs) in bronchoalveolar lavage fluid (BALF) and perilipin as a marker of lipid droplets in endobronchial biopsies were analysed according to asthma severity and BMI. Finally, peripheral blood mononuclear cells (PBMCs) were used to study the effect of BMI on steroid sensitivity in patients with asthma using an in vitro model and the effects of adipokines (leptin, resistin and adiponectin) on the release of pro-inflammatory cytokines and corticosteroid response were assessed. Severe asthmatics are often overweight (29.3%) or obese (48.3%). Increasing BMI was associated with increasing medication use in terms of short-acting β2-agonist (SABA) use per day, nebulisers and oral corticosteroid requirements (both maintenance and short burst therapy). In addition, obese severe asthmatics reported greater gastro-oesophageal reflux disease (GORD) and were less likely to be in full time employment due to their asthma. LLMs are more prevalent in subjects with GORD which may explain the higher lipid laden macrophage index (LLMI) score seen in severe compared to mild/moderate asthmatics. Perilipin was expressed in the airway epithelium and submucosa in approximately half the study population. Greater expression was seen in the submucosa of asthmatic subjects compared to healthy controls. However, no significant correlations were noted in terms of asthma severity or BMI. Leptin, resistin and adiponectin were pro-inflammatory, in terms of CXCL8 release from PBMCs taken from asthmatics and healthy controls. PBMCs taken from severe asthmatics were less responsive to steroid suppression. Adiponectin induced IL-6, IL-10, CCL2, CCL3 and TNF-α release from PBMCs taken from asthmatics and healthy controls and IFN-γ, IL-1RA, CCL2, CCL3 and TNF-α release was suppressed by dexamethasone. Adiponectin induced CCL2 release and demonstrated relative corticosteroid insensitivity at dexamethasone 10-7 M in the severe asthma group. In conclusion, obesity related severe asthma is associated with more symptoms, a significant societal impact and patients are at risk of the many deleterious side effects of corticosteroid use. Leptin, resistin and adiponectin are pro-inflammatory and adiponectin may play an important role in modulating corticosteroid sensitivity.
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Rask-Andersen, Mathias. "Obesity Genetics : Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass." Doctoral thesis, Uppsala universitet, Funktionell farmakologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-204449.
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Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. Twin studies have demonstrated a high heritability for obesity. The subsequent appli-cation of genome wide association studies (GWAS) in the last decade have identified at least 32 genetic loci associated with body mass and obesity. Despite these great advances, these loci are almost exclusively completely naïve in a functional context. Genetic variations within the gene encoding the fat mass and obesity associated gene (FTO) are the strongest and most consistently observed genetic variants associated with obesity and body mass throughout various studied populations from all parts of the world. The identification of association of FTO with obesity has spurred immense interest in the function of the FTO protein and the functional consequences of its variants. However, the implications of genetic variants at other genetic loci on protein molecular function and body mass development remain undetermined. This thesis aims to examine more closely four of the genetic loci associated with obesity; in proximity of, or associated with: FTO, TMEM18, MAP2K5 and STK33, in two cohorts of children of European descent: a case-control of clinically obese children and normal weight controls from the Stockholm area; and a cross sectional cohort of Greek children. These smaller cohorts allow for studies of more specific effects of genetic variants as individuals in these cohorts can be more carefully studied. TMEM18 gene expression was also studied in the rat-brain where a positive correlation was observed between the body weight of the animal and TMEM18 expression. We also employed next generation sequencing to more carefully study obesity-associated genetic loci related to FTO and TMEM18. We utilized a novel strategy in this project to study genetic variation in the entire FTO- and TMEM18 genes, as well as in the GWAS-identified BMI-associated loci located downstream from TMEM18. This analysis was performed on a case-control cohort of Swedish children (n = ~1000). Through this analysis, we were able to observe genetic variants within intron 1 of the FTO gene to be the main genetic variants asso-ciated with obesity at this locus. We also observed, for the first time, obesity-associated genetic variants within the gene encoding TMEM18. To analyze the potential functional context of FTO we used an in silico approach, utilizing public information databases on mRNA co-expression and protein-protein interaction. Based on our findings, we speculate on a wider functional role of FTO in extracellular ligand-induced neuronal plasticity, possibly via interaction or modulation of the BDNF/NTRK2 signaling pathway.
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McMurray, Fiona. "Investigating the role of the fat mass and obesity associated gene (Fto) in obesity." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:d7b76f58-6206-47fc-a208-7eeefac7fe27.
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In 2007, a genome wide association study identified a SNP in intron 1 of FTO with increased BMI. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. Mouse models have been made, including a conditional knockout, which is lean when globally expressed, as well as a conditional overexpression allele, which has increased body weight when globally expressed. The results from these and other studies suggest that the FTO SNPs lead to weight gain by increasing FTO activity and/or expression. Adult inactivation of Fto using the tamoxifen inducible Cre demonstrated that removal of Fto may be as deleterious as overexpression, with the adult knockout mice having increased fat mass and decreased lean mass. It also supported the role FTO plays in development as adult inactivation of Fto did not increase mortality rates as seen in the global Fto-/- pups. This study also revealed the importance of effective energy expenditure analysis in the mouse. I have confirmed a link between Fto-/- and increased mortality, which may be caused by alterations to developmental processes. Fto-/- reduces cilia formation in MEFs and results in dysregulated cilia formation in specific tissues in Fto-/- embryos. Levels of FTO also appear to affect adipogenic differentiation, which could be due to altered WNT/β-CATENIN signalling. Pharmacological inhibition of FTO was a success in vitro and a compound screen identified FG2216, which could be used in vivo to inhibit FTO. The in vivo effects of FG2216 at 60 mg/kg/2days did not affect body weight or composition in the mouse. My research suggests that there is dysregulation of gut hormones and neuronal signalling pathways in the FTO overexpression mice, which could cause the hyperphagia and increased body weight. These studies add to our current knowledge of FTO function, and suggest a role for FTO in control of body composition, development, and satiety signalling.
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Williams, Simon Robert Pask. "The physique associated with coronary artery disease." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250507.
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Saxena, Swati. "Obesity associated colon tumorigenesis: An assessment of tumor phenotype." Thesis, University of Waterloo, 2006. http://hdl.handle.net/10012/2980.
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Colon cancer and obesity are two significant and related pathological states with multiple etiological factors. In this dissertation, it was hypothesized that tumor growth is accelerated in the altered state of obesity due to their resistance towards tumor necrosis factor-alpha (TNF-alpha) mediated cytotoxicity. Physiologically elevated TNF-alpha in an obese state induces increased nuclear transcription factor-kB (NF-kB) activity, known to transcribe genes crucial to cell survival. Insulin resistance, oxidative stress, and a pro-inflammatory environment are few of the biological consequences of TNF-alpha and NF-kB pathway activation, and further contribute to disease progression. <br /><br /> Three major studies were conducted to investigate phenotypical changes in obesity associated tumors. Firstly, characteristics of the TNF-alpha resistant phenotype were preliminarily assessed by evaluating the effects of exogenous TNF-alpha treatment to HT-29 cells. Elevated levels of NF-kB in response to exogenous TNF-alpha gave an indication that this pathway is critical for cell survival. Furthermore, upregulation of TNF-alpha receptor 2 (TNFR2) suggested another strategy by which the cells were utilizing exogenous TNF-alpha for a survival advantage. Inhibition of NF-kB via St. John?s Wort treatment demonstrated that HT-29 cells may be sensitized towards TNF-alpha mediated cytotoxicity. <br /><br /> Zucker obese (Zk-Ob), Zucker lean (Zk-Ln), and Sprague Dawley (SD) animal models were used to assess tumor phenotype <em>in vivo</em>. Remarkable physiological differences between genotypes were observed. Zk-Ob rats had significantly higher body and organ weights as well as plasma TNF- alpha, insulin, leptin, and oxidative markers than Zk-Ln and SD animals. Tumor incidence and multiplicity were also notably higher in Zk-Ob rats. Protein analyses demonstrated increased levels of TNF-alpha, TNFR2, NF-kB, IkB kinase beta (IKKbeta), insulin receptor (IR), insulin like growth factor-I-receptor (IGF-IR), and mitogen activated protein kinase (MAPK) in Zk-Ob tumors than Zk-Ln counterparts. In all groups, tumors generally had higher protein expression than surrounding, normal appearing colonic mucosa. It is well known that these molecules are involved in signaling pathways that influence and co-operate with each other in rendering growth autonomy to tumor tissue. <br /><br /> A higher number of lesions in the distal than proximal colon in Zk-Ob rats was observed, supporting the emerging concept that genotype/physiological state of the host affects development and distribution of tumors. Thus, a third study was conducted to explore differences between distal and proximal tumor phenotype. Results demonstrated that expression of TNFR2, NF-kB, IR, IGF-IR, and MAPK p44 were significantly higher in distal than proximal tumors. This observation suggested that development of tumors in different regions of the colon varied under the same physiological conditions. Moreover, phenotype of distal tumors appeared to be upregulating survival pathways in comparison to proximal lesions, possibly explaining the higher tumor incidence in the distal colon. <br /><br /> Research documented in this thesis supported the hypothesis that the physiological status of the host intricately affects tumor phenotype. In particular, the TNF-alpha resistant phenotype was most prominent in Zk-Ob tumors, and appeared to be associated with upregulation of multiple signaling pathways cooperating towards tumorigenesis.
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Cabré, Casares Noemí. "Assessing Diagnostic and Therapeutic Targets in Obesity-Associated Liver Diseases." Doctoral thesis, Universitat Rovira i Virgili, 2019. http://hdl.handle.net/10803/667718.
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Les alteracions hepàtiques, com la malaltia del fetge gras no alcohòlic (NAFLD) i l'esteatohepatitis no alcohòlica, o NASH, s'associen freqüentment amb l'obesitat. L'absència de marcadors no invasius per al diagnòstic de NASH dificulta la pràctica clínica i el desenvolupament de tractaments farmacològics. Per investigar els mecanismes moleculars d'aquestes alteracions i identificar les molècules que podrien usar-se com a possibles dianes terapèutiques, busquem marcadors biològics no invasius d'alteracions hepàtiques en pacients amb obesitat tipus III sotmesos a cirurgia bariàtrica (CB). En el nostre primer estudi, vam demostrar que la funció hepàtica millora significativament després de la CB a través de mecanismes que impliquen la reducció de l'estrès oxidatiu i els processos inflamatoris. En el segon estudi, mitjançant metabolòmica dirigida vam observar que els perfils plasmàtics van identificar connexions entre el metabolisme hepàtic i l'obesitat mòrbida. Els models combinats de mesuraments en plasma simples o aparellades de alpha-cetoglutarat, beta-hidroxibutirat, piruvat i oxalacetat van reduir la incertesa en el diagnòstic clínic de NASH i van predir la seva remissió. En el tercer estudi, es demostra que alpha-cetoglutarat és un metabòlit clau en l'homeòstasi energètica modulant el procés d’apoptosis en pacients amb NASH a través de l'activació de mTORC1. Després de la CB, la desregulació metabòlica i l'autofàgia compromesa en pacients amb NASH va ser restaurada per complet. L'activació d'AMPK en els hepatòcits va anul·lar l'efecte de l'activació de la glutaminolisis i promou l'ús d'inhibidors de mTORC1. Finalment, confirmem que els metabòlits poden promoure canvis epigenètics que afecten la metilació de l'ADN i les possibles modificacions post-traduccionals en els enzims que regulen el metabolisme energètic del fetge. L'estrès oxidatiu, la disfunció mitocondrial i la mort cel·lular estan implicats en la malaltia de la NAFLD mitjançant la reprogramació metabòlica. En conclusió, alpha-cetoglutarat podria ser un nou marcador biològic potencial i una estratègia terapèutica de NASH.<br>Las alteraciones hepáticas, como la enfermedad del hígado graso no alcohólico (NAFLD) y la esteatohepatitis no alcohólica, o NASH, se asocian frecuentemente con la obesidad. La ausencia de marcadores no invasivos para el diagnóstico de NASH dificulta la práctica clínica y el desarrollo de tratamientos farmacológicos. Para investigar los mecanismos moleculares de estas alteraciones e identificar las moléculas que podrían usarse como posibles dianas terapéuticas, buscamos marcadores biológicos no invasivos de alteraciones hepáticas en pacientes con obesidad tipo III sometidos a cirugía bariátrica (CB). En nuestro primer estudio, demostramos que la función hepática mejora significativamente después de la CB a través de mecanismos que implican la reducción del estrés oxidativo y los procesos inflamatorios. En el segundo estudio, mediante metabolómica dirigida observamos que los perfiles plasmáticos identificaron conexiones entre el metabolismo hepático humano y la obesidad mórbida. Los modelos combinados de mediciones en plasma simples o pareadas de alpha-cetoglutarato, beta-hidroxibutirato, piruvato y oxaloacetato redujeron la incertidumbre en el diagnóstico clínico de NASH y predijeron su remisión. En el tercer estudio, demostramos que alpha-cetoglutarato es un metabolito clave en la homeostasis energética modulando el proceso de apoptosis en pacientes con NASH a través de la activación de mTORC1. Después de la CB, la desregulación metabólica y la autofagia comprometida en pacientes con NASH fue restaurada por completo. La activación de AMPK en los hepatocitos anuló el efecto de la activación de la glutaminolisis y apoya el uso de inhibidores de mTORC1. Finalmente, confirmamos que los metabolitos pueden promover cambios epigenéticos que afectan la metilación del ADN y las posibles modificaciones postraduccionales en las enzimas que regulan el metabolismo energético del hígado. El estrés oxidativo, la disfunción mitocondrial y la muerte celular están implicados en la enfermedad de la NAFLD mediante la reprogramación metabólica. En conclusión, alpha-cetoglutarato podría ser un nuevo marcador biológico potencial y una estrategia terapéutica de NASH.<br>Hepatic alterations, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are frequently associated with obesity. The absence of non-invasive markers for NASH diagnosis hampers clinical practice and the development of pharmacological treatments. In order to investigate the molecular mechanisms of these alterations and to identify molecules that could be used as potential therapeutic targets we search for noninvasive biomarkers of liver alterations in patients type III obesity undergoing bariatric surgery (BS). In our first study we showed that the liver function of patients with obesity are significantly improved after BS through mechanisms that involve the reduction of oxidative stress and inflammatory processes. In the second study we performed measurements in obese patients undergoing BS to identify specific metabolic patterns and to test the diagnostic ability to distinguish between patients with and without NASH. Targeted plasma metabolic profiles identified connections between liver metabolism and morbid obesity. Combined models of single or paired plasma measurements of alpha-ketoglutarate, beta-hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH and predicted NASH remission. In the third study we demonstrated that alpha-ketoglutarate is a key metabolite of energy homeostasis that modulates hepatocyte death in NASH patients through mammalian TORC1 (mTORC1). After BS, the mitochondrial oxidative metabolism and the autophagy-lysosomal function compromised in NASH patients, were also completely restored. AMPK activation in hepatocytes abrogated the effects of glutaminolysis supports the potential use of mTORC1 inhibitors. Finally, we confirm that metabolites may promote epigenetic changes affecting DNA methylation and likely post-translational modifications on enzymes regulating liver energy metabolism. Oxidative stress, mitochondrial dysfunction and cell death responses are implicated in NAFLD diseases via metabolic reprogramming. In conclusion, alpha-ketoglutarate could be a new potential biomarker and therapeutic strategy of NASH.
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Smajlovic, Dzenan. "Bestämning av FTO (Fat mass and obesity associated gene) polymorfism." Thesis, University of Kalmar, School of Pure and Applied Natural Sciences, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:hik:diva-804.
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<p>Vetenskapen har på senare år försökt fastställa de olika orsaker som leder till fetma. Det är känt att högt energiintag och för lite motion för eller senare hos de flesta individer resulterar i fetma. Det som kan konstateras är att ärftlighet i samspel med miljön vi lever i och påverkas av kan vara den huvudsakliga orsaken till en rad sjukdomar inklusive fetma. På senare år har forskare upptäckt olika gener som på ett eller annan sett är involverade i ämnesomsättningen. En sådan gen är ”fat mass and obesity associated gene”, FTO. Denna gen återfinns på kromosom 16 och har en storlek på 410 kilobaspar. Genen består av nio kodande områden, exoner, och 8 icke kodande områden, introner. Genens funktion är inte fastställd men den tycks både reglera ämnesomsättningen och lipolysen i kroppen. Tidigare studier har konstaterat att en specifik polymorfi i nukleotid rs9939609 medför ökad risk för sjuklig fetma. Uppsättningen som förekommer i nukleotiden uttrycks med A och T. Där dubbel uppsättning av A- allelen klassas som ärftlig risk för fetma. Syftet med detta examensprojekt är att bestämma polymorfi hos FTO genen med hjälp av två olika pyrosekvenserings- baserade metoder. Metod 1 bygger på extraktion av DNA från helblod, sedan amplifiering med PCR och slutligen pyrosekvensering. Metod 2, som jämfördes med metod 1, bygger på PCR direkt på helblod och pyrosekvensering. Blod från 97 friska individer analyserades. Med metod 1 konstaterades förekomst av följande genotyper i provmaterialet, 11 A/A homozygota, det vill säga har riskallelen för fetma i dubbeluppsättning, 50 A/T heterozygota och 36 T/T, vildtyp, som står för minskad ärftlig risk för fetma respektive ingen alls. Med metod 2 som skulle testas, visade sig resultatet överensstämma med metod 1. Med metod 2 erhölls följande resultat 11 A/A, 49 A/T och 34 T/T. Med metod 2 kunde inte 3 prov analyseras. Slutsatsen som kan dras utifrån studien i detta projekt är att metod 2 är likvärdig metod 1 ur analyssynpunkt. Metod 2 är arbetsbesparande tidsmässigt och även billigare då DNA extraktionssteget inte behöver genomföras.</p><p>2008:BL10</p><br><p>Science has for a long time looked for an answer for obesity. Obesity is often explained as the problem of the energy we eat and don’t use, but obesity might also have hereditary causes, where specific genes might play an important role. One of the recent genes found is the fat mass and obesity associated gene, FTO, which is located on chormosome 16 and has a size of 410 kilobasepairs. The gene is composed of nine exons and eight introns. The function of the gene is not known in detail, but studies has indicated that the gene could play a part in regulating the metabolism and fat cell lipolysis. The purpose with this examination degree project was to compare two methods for analysis of polymorphism in the FTO gene. Method 1 is based on DNA purification from whole blood, amplification with PCR, and finally detection using pyrosequencing. In method 2 PCR is performed on whole blood directly without prior DNA purification. Pyrosequencing was used with this method also to detect the polymorphism. Earlier studies have shown that theSNP (single nucleotid polymorphism) rs9939609, is associated with increased risk for obesity. Results obtained using method 1 were, 11 individuals had the A/A genotype, 50 was heterozygous (A/T), and 36 the wild type form (T/T), that is not associated with an increased risk for obesity. With method 2, the same result as with method 1 was obtained for the 94 samples of blood analyzed; 11 A/A, 49 A/T and 34 T/T were obtained. Remaining three samples of the 97 analyzed, failed in the pyrosequencing with method 2.</p><p>The conclusions with this degreeprojcet were that method 1 and 2 gave the same results. Method 2 is recommended as it is faster and less expensive, as no prior DNA purification is needed.</p>
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Laber, Samantha. "Deciphering the function of obesity-associated regulatory elements within FTO." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:5608bad0-f089-408b-bf88-792e875f0326.
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Genome-wide association studies have repeatedly shown that the strongest association with obesity arises from variants in the first intron of FTO. The intronic FTO variant rs1421085 is within an adipocyte-specific enhancer and that risk allele carriers have increased IRX3 and IRX5 expression in early adipogenesis (Claussnitzer et al., 2015). Additionally, the same human risk variant was linked to decreased AKTIP, RPGRIP1L and FTO expression in iPSC-derived neurons (Stratigopoulos et al., 2016). These data point towards several likely causal transcripts and tissues at the FTO locus and essentially, several likely mechanisms. Importantly, whether any of the high-risk variants at the FTO locus has any effect on the organismal level has not been addressed so far. The aim of my DPhil project was to use novel gene manipulation strategies in vivo to mechanistically dissect the Fto regulatory circuitry in mouse to pinpoint causal transcripts their effector tissues and to unravel their physiological role in body weight regulation . Using publicly available as well as my own genomic data (ATAC-seq) revealed that the intronic FTO regulatory element in human adipocytes is conserved in mouse pre-adipocytes. Manipulation of the corresponding motif in mouse (by deleting 82 nucleotides at the mouse orthologous region around rs1421085) resulted in depot- and sex-specific alteration of target genes Irx3 and Irx5 in pre-adipocytes. In addition to recapitulating many of the human findings in mouse, my results further unravelled a new level of regulatory complexity at the FTO/Fto locus. When these mutant mice were put on a high fat diet, I found a reduction on overall fat-mass that could be linked to altered mRNA levels of Irx3 and Irx5 in pre-adipocytes. Using a number of genetic techniques, I further showed that Irx3 regulates several processes during adipocyte development, amongst which is modulation of mitochondrial function. In summary, my findings provide new insight into how variants in FTO intron 1 affect adipocyte development and more specifically how IRX3 affects early adipocyte differentiation.
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Gali, Brent James. "HIV and aging : age-associated chronic comorbidities among HIV-positive individuals on highly active antiretroviral therapy in British Columbia, Canada." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57000.
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Background: Highly active antiretroviral therapy (HAART) has transformed HIV from a once fatal condition into a treatable chronic disease. As people with HIV are living longer than in the past, understanding the effects of aging with HIV is of increasing importance. This dissertation aims to explore trends of several chronic diseases during the current HAART era, while also taking into consideration the impact of expanded access to HAART in British Columbia, Canada from 2000-2012.
Methods: The studies presented in this dissertation are based on administrative data collected from the Comparative Outcomes and Health Service Utilization Trends (COAST) study. Various analytical methods were used to assess trends of chronic disease incidence of six common chronic diseases: cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD)/asthma, diabetes mellitus (DM), hypertension (HTN), chronic kidney disease (CKD) and chronic liver disease (CLD). Both studies were retrospective population-based cohort studies of HIV-positive individuals whom accessed HAART and identified as HIV-positive in the COAST study database by validated algorithms. Several measures were employed to determine risks and trends of chronic disease incidence.
Results: The results of each study showed that trends and risks of chronic disease incidence were not all consistent. In the first study exploring trends of chronic diseases among 10,210 HIV-positive individuals whom had accessed HAART the adjusted incidence rate for HTN increased over time; CKD and CLD decreased over time; and no trend was observed for CVD, COPD/Asthma and DM. In the second study, among 4,840 HIV-positive individuals who initiated HAART during this period, the relative risk of CLD incidence was reduced in the post- (2006-2012) versus pre- (2000-2005) HAART expansion periods. The relative risk for CVD, DM, HTN, COPD/asthma and CKD were not statistically significant in the post expansion period.
Conclusions: Results from this dissertation provide insight on trends and risks of several comorbidities during the current HAART era. Specifically, the results of this dissertation highlight the trend towards increasing incidence of HTN and decreasing incidence of CLD among HIV-positive aging populations. Understanding how chronic comorbidities affect future disability and death among people aging with HIV is an important area of further research.<br>Medicine, Faculty of<br>Population and Public Health (SPPH), School of<br>Graduate
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Gupte, Manisha. "ROLE OF ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) IN OBESITY-ASSOCIATED HYPERTENSION." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/37.
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The purpose of this research was to determine whether adipocytes express ACE2 and its role in obesity-associated hypertension with diet-induced obesity.
To determine if ACE2 was expressed in adipose tissue and its regulation in the setting of diet-induced obesity, we fed male mice either a low fat (LF) or high fat (HF) diet acutely (1 week) or chronically ( 4 months). We demonstrated that ACE2 was regulated specifically in adipose tissue with consumption of a HF diet. However, with chronic HF feeding adipose ACE2 was dysregulated resulting in activation of the systemic RAS and increased blood pressure.
To determine the role of ACE2 in obesity-associated hypertension, we used ACE2 deficient male and female mice. Wild type and ACE2 deficient mice were chronically fed either a LF or HF diet. Metabolic parameters were measured during the entire course of the study and blood pressure was measured by telemetry at the end of the study. Results from these studies demonstrate that HF diet promotes obesity-associated hypertension in male mice which is further augmented with ACE2 deficiency. Further, ACE2 deficiency resulted in marked glucose intolerance suggesting that stimulation of ACE2 may blunt the progression of obesity-associated diabetes.
In contrast to the males, females are protected against obesity-associated hypertension. However, this protection in the females is lost with ovariectomy and ACE2 deficiency. These results suggest that female sex hormones protect the females against obesity-associated hypertension by regulating ACE2.
To define mechanisms for HF diet-induced regulation of ACE2 in adipose tissue we examined various fatty acids for their ability to regulate ACE2 mRNA abundance in 3T3-L1 adipocytes. We revealed that omega-3 fatty acids, known regulators of PPARγ, increased ACE2 mRNA abundance in adipocytes. Therefore, we examined in vitro and in vivo regulation of ACE2 in 3T3-L1 cells and adipose tissue by PPARγ receptor ligands (TZDs). Results demonstrate regulatory effects of PPARγ to promote ACE2 gene transcription. These effects were associated with changes in glucose tolerance.
Taken together, these results demonstrate that adipose ACE2 plays a protective role against obesity-associated hypertension in male and female mice and is regulated by natural and synthetic ligands of PPARγ.
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Eriksson, Anders. "Functional and Molecular Characterization of Centrally Expressed Genes Associated with Obesity." Doctoral thesis, Uppsala universitet, Funktionell farmakologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-262479.
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Obesity is a complex disorder that has reached epidemic proportions in the Western world, currently affection more than two billion people. The evidence for the genetic influence on obesity has been estimated to be as high as 70% based on twin studies. Subsequent application of genome wide association studies has identified more than 90 genes to be associated with BMI. Despite great efforts the majority of the identified genetic variants have an unknown link to BMI and lack scientific basis explaining how they affect energy balance resulting in altered body weight. This thesis aims to characterize seven BMI-associated genes, Coronin 7, Etv5, Mtch2, Nudt3, Raptor, Sh2b1 and Vps13B by performing a molecular and functional profiling in mouse, zebrafish and fruit fly. A screen analysing the regulation of the selected genes under different dietary conditions revealed altered transcript levels in mouse, zebrafish and fruit fly including a conserved regulation in all species for some of the genes. Using genetic tools the Nudt3 homolog Aps in the Drosophila CNS was knocked down and showed that Aps has a role in the regulation of insulin signaling which could explain the robust association to obesity in humans. A comprehensive in situ hybridization revealed abundant Nudt3 mRNA and protein expression throughout the brain, including in reward and feeding related regions of the hypothalamus while Nudt3 mRNA expression was significantly up-regulated in the same region of food-deprived mice. Furthermore, we were able to identify a novel molecular link between obesity and bipolar disorder. The Drosophila homologue Ets96B regulates the expression of a cellular system with links to obesity and bipolar disorder, including the expression of a conserved endoplasmic reticulum molecular chaperone complex. A connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and bipolar disorder at the molecular level. Furthermore, as the BMI associated genetic variants does not fully explain the heritability of obesity we decided to perform a genome wide DNA methylation profile where we compared normal-weight and obese preadolescent children. We found a CpG site located near Coronin 7 to have significantly lower methylation levels in obese children. Further studies showed Coronin 7 to be highly expressed in important brain regions involved in energy balance. Strong immunostaining was also seen in locus coeruleus, the main site for noradrenergic production, and injecting mice with an appetite suppressant increased the number of Coronin 7 neurons within the very same brain region. An evolutionary conserved metabolic function in Drosophila was also demonstrated by knocking down the Coronin 7 homologue Pod1 in the fruit fly adult nervous system.
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Goto, Nobuko. "Impaired CNS leptin action is implicated in depression associated with obesity." Kyoto University, 2011. http://hdl.handle.net/2433/151923.
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Keast, Debra Rose. "Patterns of beverage consumption associated with adolescent obesity in the U.S." Diss., Connect to online resource - MSU authorized users, 2006.
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Thesis (Ph. D.)--Michigan State University. Dept. of Food Science and Human Nutrition, 2006.<br>Title from PDF t.p. (viewed on June 19, 2009) Includes bibliographical references (p. 260-289). Also issued in print.
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Thomas, Kerri Nicole. "An investigation of the pertinent factors associated with overweight and obesity." Phd thesis, Australian Catholic University, 2012. https://acuresearchbank.acu.edu.au/download/46cb654c7af975b064e40ec7571134c11cc8ed5f62f6ebb87b0d27d54f25c5f4/2700162/65107_downloaded_stream_332.pdf.
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The prevalence of obesity is increasing at such an alarming rate worldwide that the World Health Organisation (WHO) has declared it a global epidemic. Recent epidemiological data from WHO forecasts that by 2015, approximately 2.3 billion people will be overweight or clinically obese. Obesity is stigmatised on both health and aesthetic grounds, and is associated with serious health impairments, psychosocial consequences, and a shortened life span. As a result, eating pathology has become a central focus of current health prevention. Adding further strain to the pandemic is the pervasive finding that obesity is largely resistant to treatment. Research has shown that losing 5-10% of body weight produces significant physical and psychosocial effects, provided the weight-loss is maintained. However, extant research has consistently found that weight-loss is almost always regained over time. Participants in obesity treatment programs typically regain approximately 50% in the first year following the cessation of treatment, and by three to five years following treatment, 80% of participants have regained all of the weight lost, and have frequently exceeded their pre-treatment weight. These results have necessitated new approaches to the treatment of obesity. Recent research has revealed that targeting the psychological factors associated with body weight and training individuals in acceptance and mindfulness skills have been effective for weight-loss. The aims of this thesis were twofold. First, it aimed to investigate the pertinent factors that are associated with overweight and obesity. Second, it aimed to examine the efficacy of a pilot obesity treatment program using dialectical behaviour therapy principles. Three studies are included in this thesis. First, a broad range of biological, social, environmental, and psychological factors that have been shown to be associated with body weight were explored. The results from Study 1 indicated that the psychological influences on body weight were the most pertinent factors differentiating healthy weight individuals from overweight and obese individuals. In particular, overweight and obese individuals demonstrated lower levels of self efficacy for weight related and health behaviours, greater difficulty in controlling overeating in response to negative affect and to different social contexts. Moreover, overweight and obese participants were shown to be less likely to employ self monitoring techniques. Subsequently, Study 2 investigated additional psychological factors by examining whether there were differences between healthy weight individuals and overweight and obese individuals with regard to self-esteem, body esteem, and sociocultural attitudes towards appearance. The findings from this study revealed that body esteem was the most prominent factor distinguishing healthy weight individuals from their overweight or obese counterparts. Thereafter, the results of Study 1 and Study 2 formed the rationale for the development of a pilot DBT-informed obesity treatment program using six case studies. Study 3 investigated whether dialectical behaviour therapy may be useful in addressing these psychological factors to achieve slow weight-loss that can be maintained over time. There were four main findings from this study. First, the trend in scores highlighted a positive link between body esteem and weight-loss. As participants lost weight over time, their satisfaction with body weight and appearance also increased. Second, five out of six participants demonstrated an increase in self-monitoring, which suggests that self-monitoring of weight and health-related behaviours is relevant to weight-loss. Third, the results reveal that a two-day workshop is insufficient time to adequately address the negative emotions that individuals reported experiencing. Finally, five out of six participants demonstrated weight-loss between baseline and six-months post-treatment. Notably, two participants from the treatment group reported substantial weight-loss of nine kilograms and twelve kilograms. Participants in the active control group reported small weight-loss of two kilograms, three kilograms, and five kilograms, respectively. These results suggest that the treatment had some impact on weight-loss, although it is unknown which aspect of the treatment that may be. It is recommended that future research use a randomised controlled trial to investigate the efficacy of a DBT-informed of longer duration with a large sample size, expert DBT clinicians facilitating the treatment groups, and exclude comorbid mental health disorders. While it is expected that obesity treatments will continue to improve, a focus on prevention and early intervention is recommended to halt the current global obesity epidemic.
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Weigel, Luise. "Do adults with Prader-Willi Syndrome have psychological characteristics associated with an eating disorder?" Thesis, University of East Anglia, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300066.
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Abdalla, Thaer S. A. [Verfasser]. "The effect of non-alcoholic steatosis hepatitis on weight-loss and resolution of obesity-related comorbidities after bariatric surgery / Thaer S. A. Abdalla." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1230555110/34.
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Menegon, Dóris Baratz. "Avaliação de comorbidades em pacientes com psoríase." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/35888.
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Introdução: A psoríase é uma doença inflamatória crônica, que afeta a pele, couro cabeludo, unhas e ocasionalmente as articulações. A prevalência da psoríase varia de 0,6 a 4,8% na população mundial, afetando homens mulheres igualmente. A doença tem sido associada a um maior risco de desenvolvimento de várias comorbidades. O objetivo desse estudo é avaliar a associação entre psoríase e a presença de comorbidades como hipertensão, diabetes, dislipidemia, obesidade, depressão e os hábitos de fumar e ingerir bebidas alcoólicas. Métodos: Estudo caso-controle (psoríase x não psoriásicos) realizado no ambulatório de Dermatologia do Hospital de Clínicas de Porto Alegre. Foram avaliados os parâmetros de: peso, altura, pressão arterial, circunferência abdominal e diagnóstico de comorbidades. Nos pacientes com psoríase avaliou-se também a estimativa da área corporal acometida. Resultados: O estudo incluiu 350 casos (55,1% mulheres) e 346 controles (63,6% mulheres). A média de idade dos casos em anos foi 49,81 e nos controles 48,5. Os fatores de riscos que apresentaram diferença significativa entre casos e controles estudados foram: cintura abdominal aumentada com p<0,01 e OR=2,1 (IC 95%1,3-3,3); o Índice de Massa Corporal p=0,01 e OR= 1,8 (IC 95%1,1-2,9), tabagismo com p<0,01, OR=2,1 (IC 95%1,4-2,9) e depressão com p < 0,01 e OR=2,1 (IC 95%1,4-3,2). As variáveis triglicerídeos e o consumo habitual de álcool perderam a significância após ajuste para e idade, assim como a hipertensão. Colesterol HDL, diabetes, cardiopatia e comorbidades não listadas não mostraram diferença significativa na amostra. Ao compararmos os pacientes com estimativa de acometimento da área corporal menor e maior que 20%, as comorbidades hipertensão (p=0,03 e OR=1,69 (IC 95% 1,1 - 2,6) e diabetes (p<0,01 e OR= 2,9 (IC 95%1,6-5,4) mostraram diferença significativa. O tabagismo foi mais significativo entre os pacientes com estimativa de acometimento da área corporal menor que 20% (p<0,01 e OR 0,5 (IC 95% 0,3-0,8). As demais variáveis (cardiopatia, síndrome metabólica, depressão, comorbidades não listadas, uso de álcool, cintura abdominal alterada, Índice de Massa Corporal > 25kg/m2, triglicerídeos e colesterol HDL) não mostraram diferença entre os pacientes com maior e menor acometimento da área corporal. Conclusão: Nossos resultados confirmam a prevalência de significantes comorbidades em pacientes com psoríase quando comparado com os controles. Estes achados reforçam a necessidade da implementação de uma rotina de rastreamento para riscos metabólicos e cardiovasculares, assim como orientações sobre o estilo de vida e hábitos saudáveis.<br>Introduction: Psoriasis is a chronic inflammatory disease that affects the skin, scalp, nails and occasionally the joints. The prevalence of psoriasis varies from 0.6 to 4.8% of the world population and affects men and women alike. The disease has been associated with an increased risk of several comorbidities. The aim of this study is to evaluate the association between psoriasis and comorbidities such as hypertension, diabetes, metabolic syndrome, dyslipidemia, obesity, depression, smoking and alcohol use. Methods: A case-control study (psoriasis vs. no psoriasis) conducted in the Dermatology Outpatient Service of the Hospital de Clinicas de Porto Alegre. The evaluated parameters were: weight, height, blood pressure, waist circumference and diagnosis of comorbidity. In the patients with psoriasis the affected body surface area was also evaluated. Results: The study included 350 cases (55.1% women) and 346 controls (63.6% women). The average age was 49.81 years in the cases and 48.5 in the controls The risk factors that showed significant differences between the studied cases and controls were: increased waist circumference with p <0.01 and OR = 2.1 (95% CI 1.3 to 3.3), Body Mass Index p = 0.01 and OR = 1.8 (95% CI 1.1 to 2.9), smoking with p <0.01, OR = 2.1 (95% CI 1.4 to 2.9) and depression with p <0. 01, and OR = 2.1 (95% CI 1.4 to 3.2). The variables, triglycerides and habitual consumption of alcohol lost significance after adjustment for age and gender, as did hypertension. HDL cholesterol, diabetes, heart disease and non-listed comorbidities showed no significant difference in the sample. When comparing patients with an estimated involved body surface area smaller and larger than 20%, the comorbidities, hypertension (p = 0.03 and OR = 1.69 (95% CI 1.1 - 2.6) and diabetes (p <0.01 and OR = 2.9 (95% CI 1.6 to 5.4) showed a significant difference. Smoking was more significant among patients with an estimated involved body surface area of less than 20% (p <0.01 and OR 0.5 (95% CI 0.3-0.8). With the other variables (heart disease, metabolic syndrome, depression, non-listed comorbidities, alcohol use, altered waist circumference, Body Mass Index > 25kg/m2, triglycerides and HDL cholesterol) there was no apparent difference between patients with smaller or larger affected body surface areas. Conclusion: Our results confirm the significant prevalence of comorbidities in psoriasis patients compared with controls. The patients with more than 20% of the BSA affected are 1.69 times more likely to have hypertension and 2.9 times more likely to have diabetes. These findings reinforce the need to implement routine screening for metabolic and cardiovascular risks, as well as guidance on lifestyle and healthy habits.
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Dachtler, Jennifer Pamela. "Treatment of morbid obesity, insulin resistance and other associated risks by surgery." Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418725.
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Crawford, Sean A. "Obesity-associated diabetes, the human AMPKgamma3 R225W mutation and skeletal muscle metabolism." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28215.
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The prevalence of obesity and type 2 diabetes mellitus (T2DM) is increasing worldwide at an unprecedented pace. The fundamental understanding of the molecular mechanisms underlying the pathogenesis of these diseases is essential for the development of novel therapeutics. The objective of this work was to characterize skeletal muscle metabolism of obese subjects with a history of T2DM and that of subjects carrying the AMP-activated protein kinase (AMPK) gamma3 R225W mutation. Primary myotubes from obese subjects with a history of T2DM showed defects in mitochondrial biogenesis, oxidative capacity and in mechanisms known to mitigate oxidative stress. Conversely, primary myotubes from subjects carrying the AMPKgamma3 R225W mutation had elevated mitochondrial content and oxidative capacity relative to matched controls. R225W carriers also showed evidence of increased muscle glucose uptake in vivo and in vitro, leading to the conclusion that AMPKgamma3 may represent an effective novel pharmaceutical target for treatment of T2DM.
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Bailey, Swneke. "Genetic insights into obesity and its associated metabolic complications: a multiethnic perspective." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104623.
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Obesity has become one of the biggest threats to global health, as it frequently co-occurs with a constellation of type 2 diabetes (T2D) and cardiovascular disease (CVD) risk factors and is associated with increased mortality. Genetic factors account for a substantial portion of the phenotypic variance in obesity and each of the correlated vascular disease risk factors. In this thesis, I describe the identification of several common genetic variants that predispose carriers to the complications associated with obesity. First, I report the identification of common variation within the gene of a protein secreted by visceral adipose tissue, visfatin, and demonstrate the influence of these variants on the inter-individual variation in fasting insulin levels. Second, I describe the identification of an interaction between the use of thiazolidinediones (TZDs), a class of anti-hyperglycemic medication, and variation in the nuclear factor of activated T-cells cytoplasmic component 2 (NFATC2) gene that results in edema and potentially congestive heart failure (CHF). Next, using a South Asian population sample for gene discovery, I identify a novel association between variation in the dipeptidyl peptidase 4 (DPP4) gene, a target of incretin-based anti-hyperglycemic medication, and apolipoprotein B (apoB) levels, a CVD risk factor and marker of the dyslipidemia associated with obesity. In addition, using observed differences between the Europeans and South Asians I was able to identify heterogeneity in the association between DPP4 and apoB caused by adiposity. Finally, I report an association between variation in the sterol regulatory element binding protein 1 (SREBF1) gene and body mass index (BMI) and demonstrate its potential contribution to observed differences in BMI among different ethnicities around the world. I also present data that strongly suggest that these differences may have been due to recent positive selection at this locus in human populations. The findings in this thesis illustrate the importance of common genetic variants in the pathogenesis of obesity, as well as its associated complications and highlight the regulation of glucose by adipose tissue as an important underlying feature.<br>L'obésité est devenue une des plus grandes menaces dans la santé publique, étant donné qu'elle est fréquemment co-reliée avec des facteurs de risque du diabète de type 2 (T2D) et de la maladie cardiovasculaire (CVD), et est donc associée à une mortalité accrue. Les facteurs génétiques représentent une partie substantielle de la variation phénotypique de l'obésité, ainsi que des facteurs de risque des maladies vasculaires qui y sont associés. Dans cette thèse, je décris l'identification de plusieurs variants génétiques communs qui prédisposent les porteurs aux complications associées à l'obésité. D'abord, je décris l'identification d'une variation commune dans le gène d'une protéine sécrétée par le tissu adipeux viscéral, visfatin, et démontre l'influence de ces variants sur la variation interindividuelle d'une insulinémie à jeun. Deuxièmement, je décris l'identification d'une interaction entre l'utilisation des thiazolidinediones une classe de médicaments anti-hyperglycémiques, et une variation génétique dans le gène nuclear factor of activated T-cells cytoplasmic component 2 (NFATC2) qui aboutit à l'œdème et potentiellement à l'insuffisance cardiaque congestive. Ensuite, en utilisant un échantillon de la population asiatique du Sud dans la découverte de gènes, j'identifie une nouvelle association entre la variation du gène dipeptidyl peptidase 4 (DPP4), une cible de la médication anti-hyperglycémique basée sur l'incretin, et les niveaux de l'apolipoprotéine B (apoB), un facteur de risque du CVD et un marqueur de la dyslipidémie associée à l'obésité. De plus, en utilisant des différences observées entre les Européens et les Asiatiques du Sud, j'ai pu identifier l'hétérogénéité dans l'association entre DPP4 et apoB causé par l'adiposité. Finalement, je décris une association entre la variation du gène sterol regulatory element binding protein 1 (SREBF1) et l'indice de masse corporelle (BMI) et démontre sa contribution potentielle aux différences de BMI observées parmi différentes ethnicités dans le monde entier. Je présente aussi des données qui suggèrent fortement que ces différences peuvent être dues à une récente sélection positive à ce locus dans des populations humaines. Les découvertes de cette thèse illustrent l'importance des variants génétiques communs dans la pathogenèse de l'obésité, ainsi que les complications qui s'y rattachent et mettent en évidence la régulation de glucose par le tissu adipeux comme étant une caractéristique sous-jacente importante.
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Bokhamada, Hanan. "The effect of testosterone on factors associated with diabetes, atherosclerosis and obesity." Thesis, Sheffield Hallam University, 2014. http://shura.shu.ac.uk/19365/.
Full textAbstract:
Obesity has recently become a major global health problem. Epidemiologic studies indicate that obesity is an important risk factor for type 2 diabetes (T2DM), atherosclerosis and low testosterone in men. Importantly, testosterone replacement treatment (TRT) can improve the condition of these diseases. According to human and animal studies testosterone can act as an anti-inflammatory and anti- atherogenic factor leading to inhibition of the risk factors and consequence of T2DM and atherosclerosis. Consequences of these diseases include dysregulation in atherogenic factors such as apolipoproteins or pro-inflammatory mediators such as cytokines and chemokines and their receptors. The effect of testosterone on these factors remains unclear. The objective of the present study was to demonstrate whether testosterone has antiinflammatory and anti-atherogenic action and by which mechanisms. This was achieved by using in vivo human and mice studies as well as in vitro models. The in vivo human study was conducted on short and long term studies, to determine the effect of TRT on anti and pro-inflammatory cytokines, HDL fractions and apolipoproteins in diabetic hypogonadal patients. Samples of liver tissue from testicular feminization mice (Tfm) were studied to investigate the effect of testosterone therapy on mRNA expression of adiponectin, PP ARb/o, PAI-1, apolipoproteins and pro-inflammatory chemokines with their receptors. Additionally, models of cell culture were studied including human macrophage THP-1 cells and mouse 3T3L1 cells to study the effect of testosterone with or without blocked androgen receptor (AR) on CX3CR1 and CCR2 and pro-inflammatory cytokines in macrophage cells and on adiponectin, PP ARB/o, PAI-1, leptin and chemokines in adipocyte cells, respectively. In the clinical studies, a reduction in adiponectin levels after 3 months was seen in the short-term study and an increase in HDL2 and HDL2/HDL3 ratio in the long-term study. No significant effect of testosterone was observed on body composition and atherogenic factors in either the short or long-term studies. In the animal study, testosterone increased hepatic expression of mRNA adiponectin, PP ARB/o and PAI-1 mRNA expression in Tfm. In the cell culture studies, testosterone treatment increased CCR2 mRNA expression and decreased secretion of IL-8 and TNF level in the supernatant of THP-1 macrophages. Testosterone decreased secretion of CCL2 and CX3CL1 from 3T3L1 adipocytes while increasing PAI-1 mRNA expression in these cells. The action of testosterone was based on the type of cells and time, route and dose size of treatment. In conclusion, although testosterone therapy showed a positive effect on some risk factors of obesity and its associated conditions, negative effects were also seen. However the exact mechanism of action of testosterone that influences risk factors of obesity and its associated conditions in men with low testosterone remain unclear, therefore further studies are needed to fully elucidate the above finding.
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Giles, Daniel. "Interrogating the mechanisms underlying the immunopathogenesis of obesity and its associated sequelae." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1493714792971456.
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Sun, Antonia Rujia. "Macrophage-mediated synovial inflammation is a key link to obesity-associated osteoarthritis." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/123711/1/Antonia%20Rujia_Sun_Thesis.pdf.
Full textAbstract:
Obesity has been attributed in a major risk factor for developing and accelerating disease progression in osteoarthritis. To date, there is a lack of clinically proven therapies to halt osteoarthritis, the developments of such therapies are therefore a national as well as an international research priority. This research provides a new overview of the involvement of synovitis in promoting the destruction of synovial joints in obesity-induced osteoarthritis and might therefore by used as a therapeutic strategy for the development of disease-modifying anti-osteoarthritis drugs.
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Tan, Mun Chieng. "Multidisciplinary surgical management of patients with clinically severe obesity in a publicly funded bariatric surgery service in three public hospitals in Australia." Thesis, University of Sydney, 2021. https://hdl.handle.net/2123/24521.
Full textAbstract:
Background:
Obesity, a National Health Priority Area, has been a major challenge facing the Australian population and is at a crisis level. It has also become a global epidemic with a disproportionate rise in class III obesity (BMI ≥40 Kg/m2), causing substantial burden in obesity and the healthcare systems. There are approximately one million adults in Australia with clinically severe obesity, defined as class III obesity alone or a BMI ≥35 Kg/m2 with at least one major obesity-related comorbidity. Bariatric surgery is well-established as the most effective treatment for severe and complex obesity that has been unmanageable by other modalities. Despite most Australians relying on the public healthcare system, the vast majority of bariatric surgical procedures are performed in private hospitals owing to scarce resources in the public sector. As a result of this reason and sparse research funding, there is a limited understanding of the management, benefits and safety of publicly funded bariatric surgery in the context of clinically severe obesity and its metabolic consequences, especially in long-term (defined by >5 years).
Settings:
A multidisciplinary publicly funded bariatric surgery service covering three public hospitals, namely Royal Prince Alfred Hospital, Concord Repatriation General Hospital and Camden Hospital in Sydney, New South Wales (NSW), Australia. Data linkage with the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) was also performed.
Aims and research themes:
This thesis aims to address key knowledge deficiencies in a broad range of areas encompassing the full spectrum of bariatric surgery in multidisciplinary clinical obesity services, using both retrospective and prospective study designs. These studies were grouped into four major research themes, with each theme representing one chapter in the thesis. The research themes investigated were: (1) long-term health outcomes after bariatric surgery, (2) adherence to multidisciplinary post-operative follow-up care, (3) whether pre-operative weight loss predicts post-surgical weight loss, and (4) prediction of diabetes remission using an algorithm.
Main findings:
The first research theme (CHAPTER 2) is a retrospective cohort study that examined the long-term effectiveness and safety of bariatric surgery in a highly-complex clinically severe obese population. While the overall weight loss and changes of obesity-related comorbidities [especially type 2 diabetes mellitus (T2DM), hypertension and hyperlipidaemia] were significant following bariatric surgery over 6 years; being super obese (BMI ≥50 Kg/m2) had no multiplicative and detrimental effect in these features compared to the morbidly obese patients (<50 Kg/m2). The prevalence of the obesity-related comorbidities studied [i.e. T2DM, hypertension, osteoarthritis (OA) and/or weight-bearing joint pain (WBJP), sleep-disordered breathing and hyperuricaemia] decreased after bariatric surgery and remained lower than baseline as time progressed; whereas hyperlipidaemia and mental illness surpassed baseline level at post-operative 6 years. For nutrient deficiency, vitamin D deficiency was noted in one-third of patients pre-operatively and decreased significantly after bariatric surgery. Iron deficiency anaemia doubled at year 6 post-operation. Low prevalence of vitamin B12 insufficiency was detected before and after bariatric surgery, with no patient developing a deficiency in years 5 and 6 post-operatively. Of the 34.5% with peri- and post-operative complications, none was life-threatening.
The second research theme (CHAPTER 3) is a prospectively conducted study that investigated the reasons for ceasing attendance at clinic reviews after surgery, predictors of adherence to post-bariatric surgery clinic reviews, and the relationship – if any – between adherence to follow-up and weight loss outcomes. The adherence rate to follow-up visits after bariatric surgery (i.e. patients attended follow-up regularly) among the study patients was 63.7% [107 of 168 (63.7%)]; 20 (11.9%) attended irregularly and 41 (24.4%) ceased attending reviews. According to the patients, withdrawal from the publicly funded bariatric surgery service was mainly associated with travel distance. Linear mixed-effects model with random effects revealed no pronounced difference in the mean weight loss between the adherent and nonadherent groups (composite of those who attended irregularly or who ceased attending follow-up) over the years. Logistic regression model shows that older and partnered patients were more likely to adhere to follow-up care after operation. The results could guide care practices for patients needing additional contacts and supports, so they may benefit from additional assistance to experience optimal outcomes.
Subsequent studies (CHAPTER 4) explored the relationship between pre-operative weight loss and weight loss post-bariatric surgery, to determine the necessity of the current requirement for weight loss prior to publicly funded bariatric surgery in the future. The result shows insignificant relationship between these two parameters, suggesting that the pre-operative weight management program (WMP) that is currently-mandated prior to the surgery may not be necessary. However, the WMP might still be important as an opportunity to resolve medical problems; to prevent post-operative psychological issues from emerging; to ensure patients understand the implications of bariatric surgery and its necessary lifestyle changes; and to minimise potential surgical risks. Multiple linear regression analysis demonstrated that age at surgery is a reliable predictor of post-operative weight loss across years 1 to 6 post-operation, suggesting that older patients may achieve better outcomes from bariatric surgery.
The fourth research theme (CHAPTER 5) identified short- and longer-term post-operative diabetes remission prediction following bariatric surgery using the DiaRem scoring system that computed by the following simple variables – age, HbA1c, glucose lowering treatment other than insulin, and insulin treatment. The DiaRem algorithm was shown to perform well in discriminative capacity, predictive ability and calibration in the study cohort with T2DM. The area under the curve (AUC) of the receiver operator characteristic was 0.869 (95% CI=0.800–0.938) for the standard year 1 post-operative follow-up, with the most optimal cut-off score being ≤12, sensitivity of 94.8% and specificity of 64.2%. The discriminative ability is comparatively high for those with 5-year post-operative diabetes remission [AUC=0.835 (95% CI=0.714–0.956), optimal cut-off score ≤12, sensitivity=89.5% and specificity=52.2%]. Logistic regression models demonstrated that DiaRem algorithm reliably predicted diabetes remission 1 year [OR (95% CI)=0.733 (0.655-0.821), p<0.001] and 5 years following surgery [OR (95% CI)=0.753 (0.623-0.909), p=0.003]. The Hosmer-Lemeshow goodness-of-fit tests indicated good fit of DiaRem prediction models for both 1 year and 5 years post-surgery, thus accurate models to use. This study confirmed that DiaRem is a useful and practical tool to help clinicians with selection and prioritisation of patients with T2DM and seeking bariatric surgery in publicly funded models.
Conclusion:
Collectively, this thesis highlights the unique nature of the multidisciplinary surgical management of clinically severe obesity in three specialist obesity services in public hospitals within the carefully-studied cohort. It supported the high-risk and well-characterised clinically severe obese population with long-term effective and safe access to multidisciplinary publicly funded bariatric surgery service and research. These studies significantly contributed to a transparent and improved understanding of the management in the context of complex obesity, including those with super obesity and multiple obesity-related comorbidities. Ultimately, these findings can enhance clinical practice by providing evidence-based knowledge and specific tools for the management of multidisciplinary bariatric surgery in the growing population with clinically severe obesity.
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Liu, Tsz-chiu, and 廖子超. "Lipocalin-2 is a pro-inflammatory adipokine causally involved in obesity-associated endothelial dysfunction." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45589434.
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Gruber, Tim [Verfasser], Matthias H. [Akademischer Betreuer] Tschöp, Matthias H. [Gutachter] Tschöp, and Kadow Ilona [Gutachter] Grunwald. "Targeting glia-vascular interactions for the treatment of obesity and its comorbidities / Tim Gruber ; Gutachter: Matthias H. Tschöp, Ilona Grunwald Kadow ; Betreuer: Matthias H. Tschöp." München : Universitätsbibliothek der TU München, 2020. http://d-nb.info/1221719297/34.
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Castiglione, Kate Elizabeth. "Investigations into the effect of a high-fat diet (HFD) on gastrointestinal and physiological mechanisms associated with eating behaviour." Thesis, University of Sheffield, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370054.
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Mustard, Colette J. "The impact of antipsychotic drugs on the expression of genes associated with obesity." Thesis, University of the Highlands and Islands, 2016. https://pure.uhi.ac.uk/portal/en/studentthesis/the-impact-of-antipsychotic-drugs-on-the-expression-of-genes-associated-with-obesity(3e4585b2-4892-4bed-a673-41ab0d83f673).html.
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Schizophrenia is a severe and debilitating disorder, primarily treated with antipsychotic medications. Weight gain is a serious side-effect associated with most second generation antipsychotic drugs such as clozapine. The mechanism behind clozapine-induced weight gain remains poorly understood, but changes in eating behaviour and energy homeostasis may be involved. Recently, genome-wide association studies have identified a number of genetic variants associated with obesity risk; however the effects of these risk variants on clozapine-induced weight gain have not been investigated. This doctoral thesis focused on the following research questions: (1) Does schizophrenia share a genetic link with obesity? (2) Can various antipsychotics alter the expression of obesity-related genes? (3) What is the initial signalling event by which clozapine could induce a change in mRNA expression of the obesity-related genes? The major findings from this work included that there was no demonstrable association between obesity-related variants and schizophrenia, and that low and intermediate doses of clozapine (0.125 μg/ml and 0.25 μg/ml) induced changes in mRNA expression of a panel of obesity-related genes in U937 cells. This effect was not observed in cells treated with haloperidol. However, the mRNA expression of most obesity-related genes tested was also altered by treatment with olanzapine in most obesity-related genes tested but only in one gene when treated with risperidone. Treatment with 5-HT promoted an increase in mRNA expression of some obesity-related genes, which was similar to the treatment with 0.25 μg/ml clozapine although this effect was not apparent with a combination of clozapine and 5-HT. Changes in mRNA expression in clozapine-treated cells were likely mediated by the IP3 signalling pathway. In conclusion, the mechanism behind weight gain in patients treated with either clozapine or olanzapine is multi-factorial: this study suggests that there may be an additional risk factor that could facilitate antipsychotic-induced weight gain: the altered the mRNA expression of obesity-related genes.
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Al, Hourani Huda Mustafa. "Nutritional factors associated with obesity in adolescent females in the United Arab Emirates." Thesis, Oxford Brookes University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369948.
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Padidar, Sara. "Obesity and colon cancer links : proteomic and transcriptomic investigation of associated signalling targets." Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=135783.
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This project has identified increased adiposity and altered plasma leptin levels to be not associated with colon sensitivity to a colon carcinogen using diet-induced obesity (DIO) rodent and defective leptin signalling mutant mouse models. These findings do not support a direct link between the deregulation of insulin and adipokine levels observed in obese rats with increased risk of colon carcinogenesis. However, elevated leptin levels associated with increased dietary fat intake did increase the risk of colon carcinogenesis, supporting previously reported studies. Increased adiposity was associated with altered plasma insulin, leptin and triglyceride levels and 69 mitochondrial associated proteins in DIO rats. The changes in these mitochondrial protein profiles were not correlated with changes at the gene expression level assessed using real-time PCR arrays. The rat colon mitoproteome analysis is also presented here to provide a useful tool in assisting identification and interpretation of mitochondrial dysfunction implicated in colon pathogenesis. Animal studies have shown altered leptin levels linked to obesity can disrupt normal processes in colon. The role of leptin receptors identified in the colon is unknown. Deregulation of IL6, IL1β and CXCL1 was associated with leptin signalling in colon tissue. Cross talk of leptin and insulin signalling by modulation of IGBP3, IGF2 and AKT1 were also highlighted. Leptin regulation of mitochondria-associated apoptotic pathways involving UCP2, CASP3 and CASP9 in the colon was also identified. The study presents novel strategies to dissect signalling cascades in colon influenced by obesity and links with colon cancer.
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Yang, Bo, and 杨波. "Role of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47869641.
Full textAbstract:
Obesity is closely related to many medical complications such as type 2 diabetes,
hypertension and heart failure. Obesity and other factors, including elevated blood
glucose levels, hypertension, and dyslipidemia, constitute a constellation of symptoms
known as the metabolic syndrome, which are the risk factors for coronary artery
disease. Lipocalin-2 is a pro-inflammatory adipokine causally involved in the
development of obesity-associated metabolic and cardiovascular diseases. Recent
clinical and experimental evidences demonstrate an association between augmented
circulating lipocalin-2 and cardiac dysfunction. However, little is known about the
detailed roles of lipocalin-2 in regulating pathophysiological functions of the heart.
The present study was designed to compare the heart functions of mice with normal
(WT) or deficient lipocalin-2 (Lcn2-KO) expression and to examine the molecular
mechanisms underlying lipocalin-2-mediated deteriorated effects in hearts.
Echocardiographic analysis revealed that the myocardial contractile function was
significantly improved in hearts of Lcn2-KO mice, under both standard chow and
high fat diet conditions. The heart function before and after I/R injury (20-min of
global ischemia followed by 60-min of reperfusion) was assessed using the
Langendorff perfusion system. Compared with WT littermates, hearts from Lcn2-KO
mice showed improved functional recovery and reduced infarct size following I/R.
These phenomena can be observed in mice under both standard chow and high fat
feeding conditions.
Under baseline condition, the mitochondrial function of hearts from Lcn2-KO
mice was significantly enhanced, as demonstrated by biochemical analysis of
respiratory chain activity, markers of biogenesis and oxidative stress, as well as
electron microscopic investigation of the mitochondrial ultrastructure. Acute or
chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and
dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were
associated with an extensive modification of the fatty acyl chain compositions of
intracellular phospholipids. In particular, lipocalin-2 facilitated the redistribution of
linoleic acid (C18:2) among different types of phospholipid, including cardiolipin,
which is exclusively located in the mitochondria inner membrane.
The direct effects of lipocalin-2 on both H9c2 and NCM cells were also
examined. TUNEL assay and flow cytometry analysis demonstrated that lipocalin-2
treatment promoted apoptosis in cardiomyocytes. Lipocalin-2 induced an early phase
of phosphatidylserine exposure, followed by Bax-translocation and caspase-3
cleavage. The results collectively suggested that lipocalin-2 initiated the intrinsic
mitochondria-mediated apoptotic pathway. In the hearts of Lcn2-KO mice,
significantly reduced number of apoptotic cells was observed after I/R injury.
In conclusion, lacking of lipocalin-2 improved heart function recovery during I/R
injury via mitochondrial function restoration, phospholipids remodeling, and
inhibition of cardiomyocytes apoptosis.<br>published_or_final_version<br>Pharmacology and Pharmacy<br>Doctoral<br>Doctor of Philosophy
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Cheung, Man Ka. "Investigating the cellular function of the fat mass and obesity associated (FTO) protein." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608074.
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George, Siddiqah. "A critical analysis of mitochondrial functioning and associated proteins in obesity-related cardiomyopathy." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/80377.
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Thesis (MScMedSc)--Stellenbosch University, 2013.<br>ENGLISH ABSTRACT: INTRODUCTION: The mechanism behind obesity-related cardiomyopathies is at present not completely known, however, cardiac insulin resistance has been implicated as one of the main arbitrators of obesity-related cardiovascular disease. A few studies have associated perturbations in the insulin-mediated PI3K/PKB/Akt pathway in mediating this insulin resistance. Moreover, this pathway has been shown to regulate myocardial apoptosis, which in turn has been implicated in a number of cardiovascular diseases. Currently, few studies have compared the early onset and advanced effects of obesity on the heart.
AIMS: To compare the early and advanced stages of obesity in terms of myocardial (i) PI3K/PKB/Akt signalling, (ii) apoptotic signalling and (iii) mitochondrial integrity. Furthermore, we aim to assess the cardiac mitochondrial (i) PI3K/PKB/Akt signalling, (ii) apoptotic signalling and (iii) integrity during the advanced stages of obesity.
METHODS: Male Wistar rats were randomly assigned to either a control or diet-induced obesity (DIO) group. Controls were fed a standard rat chow diet and the DIO group fed a high caloric diet (standard rat chow supplemented with sucrose and condensed milk). The diets were implemented for either 8 or 20 weeks and thereafter, the body weight, intra-peritoneal fat mass, and fasting blood glucose and insulin levels (including intra-peritoneal glucose tolerance tests (IPGTTs)) were determined. Freeze-clamped hearts from both groups were subjected to cytosolic western blot analysis for PI3K p85 subunit, PKB/Akt, GSK-3α/β, Bad, Bax and Bcl-2. A fraction of each heart was also subjected to WB analysis of the mitochondrial electron transport chain (ETC) complexes (I-V). Thereafter, the above mentioned proteins were also probed for in mitochondria isolated from the 20 weeks group after administering insulin and exposing the hearts to ischemia. Oxidative phosphorylation (OXPHOS) capacity analysis was then conducted on mitochondria isolated from 20 weeks DIO and control groups and thereafter a citrate synthase (CS) activity assay was performed on these mitochondria.
RESULTS: After the 8 and 20 weeks diet, the DIOs had significantly increased intra-peritoneal fat mass, fasting plasma glucose and insulin levels, compared to their controls. Cytosolic WB analysis: The tp85, pp85 and pPKB/Akt levels were significantly higher in the DIOs in comparison to the controls after 8 weeks of diet. Furthermore, pBad and Bax expression were significantly elevated in these animals. After 20 weeks of diet, the DIOs had significantly decreased pp85, tPKB/Akt and pPKB/Akt levels. The tBad was significantly elevated, while the Bad phosphorylated over total expression (P/T) ratio was significantly decreased, in these animals. CS activity assay: CS activity was significantly decreased in the DIOs, versus the controls, at 20 weeks. Mitochondrial ETC WB analysis: The subunit expression in complexes I-III and V did not differ significantly after 8 weeks however, the expression was significantly lower in complexes I and II after 20 weeks. Interestingly, the complexes III and V expression was significantly elevated. Mitochondrial OXPHOS analysis: The ADP/O ratio with (1) glutamate or (2) palmitoyl-L- carnitine as substrate, showed a significant decrease in the DIOs at 20 weeks. Mitochondrial WB analysis: The pp85 subunit was significantly elevated in the control and DIO groups, exposed to insulin and ischemia, in comparison to the untreated controls. The Bcl-2 levels were significantly decreased in the insulin and ischemia DIOs, when matched against the untreated DIOs. The tBad expression did not differ significantly between the insulin and untreated controls, while the tBad was significantly augmented in the ischemia controls versus untreated controls. All significant differences were taken as p<0.05.
CONCLUSION: The results indicate that the initial stage of diet-induced obesity is associated with cardioprotection as there is augmented PI3K/PKB/Akt pathway signalling and a decrease in apoptotic markers. In contrast, during the advanced stages of obesity a decreased activity in PI3K/PKB/Akt pathway is associated with myocardial apoptosis and decreased mitochondrial function and integrity.<br>AFRIKAANSE OPSOMMING: INLEIDING: Die meganisme verantwoordelik vir vetsug-verwante kardiomiopatieë is huidiglik nie bekend nie maar kardiale insulienweerstandigheid word geïmpliseer as een van die hoof bemiddelaars van vetsug-verwante hartsiektes. Verskeie studies het versteurings in die insulien-gemediëerde PI3K/PKB/Akt pad geassosieer met die bevordering van hierdie insulienweerstandigheid. Daarbenewens is dit getoon dat hierdie pad betrokke is in die regulering van miokardiale apoptose, wat op sy beurt geïmpliseer is in 'n aantal kardiovaskulêre siektes. Daar is tans min studies beskikbaar wat die vroeë en laat gevolge van obesiteit op die hart vergelyk.
DOELWITTE: Om die vroeë en gevorderde stadiums van vetsug te vergelyk in terme van miokardiale (i) PI3K/PKB/Akt seintransduksie, (ii) apoptotiese seintransduksie en (iii) mitokondriale integriteit. Verder, het die studie ten doel om die kardiale mitokondriale (i) PI3K/PKB/Akt en (ii) apoptotiese seintransduksie en (iii) integriteit in die gevorderde stadiums van vetsug te bepaal.
METODES: Manlike Wistar rotte is ewekansig toegewys aan óf 'n kontrole of dieet-geïnduseerde vetsug (DIO) groep. Kontroles is met 'n normale rotkos dieet en die DIO groep met 'n hoë kalorie dieet (normale rotkos aangevul met sukrose en kondensmelk) gevoed. Die dieet is vir 8 of 20 weke volgehou en daarna was die liggaamsgewig, intra-peritoneale vet massa, en vastende bloed glukose en insulien vlakke (insluitende intra-peritoneale glukose toleransie toets (IPGTT`s)) bepaal. Gevriesklampte harte van beide groepe is onderwerp aan sitosoliese WB-analise vir die PI3K p85 subeenheid, PKB / Akt, GSK-3α/β, Bad, Bax en Bcl-2. `n Fraksie van hierdie harte is ook onderwerp aan westerse klad analise (WK-analise) van die mitokondriale elektron vervoer ketting (EVK) komplekse (I-V). Daarna is bogenoemde proteïene ondersoek in mitokondrieë geïsoleer uit die 20 weke groep ná die toediening van insulien en die blootstelling van die harte aan iskemie. Die oksigraaf mitokondriale oksidatiewe fosforilering (OXPHOS) kapasiteit analise is dan op mitokondrieë van 20 weke DIO en kontrole groepe uitgevoer en daarna is 'n sitraatsintase (SS) aktiwiteitstoets gedoen.
RESULTATE: Na die 8 en 20 weke dieet, het die intra-peritoneale vet massa, vastende plasma glukose en insulien vlakke in die DIOs aansienlik toegeneem, in vergelyking met hul kontroles. Sitosoliese WK-analise: Die tp85, pp85 en pPKB/Akt vlakke was beduidend hoër in die DIOs in vergelyking met die kontroles, na 8 weke van die dieet. Verder is die pBad en Bax vlakke beduidend verhoog in hierdie diere. Na 20 weke van die dieet, het die pp85, tPKB/Akt en pPKB/Akt vlakke beduidend afgeneem in die DIOs, in vergelyking met die kontroles. Die tBad was beduidend verhoog, terwyl die Bad verhouding van gefosforileerde oor die totale proteïen uitdrukking (P/T)-verhouding) beduidend verminder het in hierdie diere. SS aktiwiteitstoets: SS aktiwiteit is beduidend verminder in die DIOs, teenoor die kontroles, op 20 weke. Mitokondriale EVK WK-analise: Die subeenheid uitdrukking in komplekse I-III en V was nie beduidend verskillend na 8 weke nie. Na 20 weke egter, was die uitdrukking aansienlik laer in komplekse I en II. Interessant genoeg, is die uitdrukking aansienlik verhoog in komplekse III en V. Mitokondriale OXPHOS analise: Die ADP/O verhouding met (1) glutamaat of (2) palmitiel-L-karnitien as substraat, het beduidend afgeneem in die DIOs teen 20 weke. Mitokondriale WK-analise: Die pp85 subeenheid was beduidend verhoog in die kontrole en DIO groepe, blootgestel aan insulien en iskemie, in vergelyking met die onbehandelde kontroles. Die Bcl-2 vlakke was beduidend verminder in die insulien en isgemie DIOs, in vergelyking met onbehandelde DIOs. Die tBad uitdrukking het nie beduidend verskil tussen die insulien en onbehandelde kontroles nie, terwyl die tBad beduidend verhoog was in die isgemie kontroles versus onbehandelde kontroles. Alle beduidende verskille is geneem as p<0.05.
GEVOLGTREKKING: Die resultate dui daarop dat die eerste fase van dieet-geïnduseerde obesiteit geassosieer is met kardiale beskerming want `n toename in PI3K/PKB/Akt seintransduksie en 'n afname in apoptotiese merkers is waargeneem. In teenstelling, in die gevorderde stadium van vetsug is daar 'n afname in aktiwiteit in die PI3K/PKB/Akt pad wat verband hou met verhoogde miokardiale apoptose en verminderde mitokondriale funksie en integriteit.
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Karra, E. "The role of the fat mass and obesity-associated gene in appetite regulation." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1427872/.
Full textAbstract:
FTO encodes a nucleic acid demethylase with substrate preference towards N6-methyladenosisne (m6A). Variation in the FTO gene confers the single greatest genetic risk for common obesity amongst all obesity susceptibility loci identified to date. The mechanisms via which FTO variation promotes adiposity remain unknown. Increased hunger, increased energy intake, and enhanced preference for palatable, calorically-rich foods constitute a common denominator between ghrelin signalling and FTO perturbation. Hence, we hypothesized that altered ghrelin levels mediate the FTO-related obesogenic feeding patterns, and we undertook human, rodent and cellular studies to test our hypothesis. Here we show that Caucasian males, homozygous for the high-risk allele A of FTO rs9939609 exhibit increased BMI and adiposity compared to homozygotes for the protective variant T, even within the normal BMI-spectrum; before the development of overweight and obesity. In two independent cohorts we show that normal-BMI AA subjects exhibit attenuated hunger suppression post-meal and aberrant ghrelin profile compared to adiposity-matched TT controls; with the ghrelin phenotype of normal-BMI AA subjects reminiscing ghrelin changes seen in human obesity. Moreover, we show that global Fto deletion in mice results in alterations in circulating ghrelin levels. Utilizing reward-trait assessment questionnaires we demonstrate weight-independent increases in reward responsiveness in AA subjects. Using fMRI we show that FTO genotype weight-independently alters neuronal responsiveness to visual food cues within homeostatic and reward appetitive circuitries. Furthermore, we report that peripheral blood cells from healthy normal-weight Caucasian AA males have increased FTO and GHRL mRNA relative abundance, with decreased m6A GHRL mRNA residues compared to TT controls. Finally, we show that overexpression of FTO in HeLa cells increases abundance of pre-proghrelin, pro-ghrelin and ghrelin peptides, as well as GOAT protein in the cell lysates. Collectively, these data reveal a novel link between FTO and ghrelin, and implicate ghrelin deregulation to the adipogenic effects of FTO.