Dissertations / Theses on the topic 'Obesity and metabolic disfunction'

PTX3 is a biomarker of cardiovascular diseases and exerts protective functions in acute myocardial infarction and atherosclerosis. Here we aimed at investigating the role of PTX3 in cardiovascular diseases. First we studied the role of PTX3 in arterial thrombosis induced by FeCl3 injury: PTX3 KO mice showed a 60% reduction in carotid artery blood flow with a greater thrombus formation compared to 20% of WT mice (p<0.01) following arterial thrombosis, an effect mediated by PTX3 derived from non-hematopoietic cells: indeed, PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant increased carotid occlusion compared to WT mice transplanted with bone marrow from WT or PTX3 KO mice (p<0.01). This effect was independent of altered hemostatic properties, impaired platelet activation, modulation of P-selectin activity as P-selectin KO/PTX3 KO mice showed a significant reduction in carotid artery blood flow and increased arterial thrombus formation compared to P-selectin KO (p<0.01). PTX3 was shown to localize between the damaged artery and thrombus and to reduced platelet aggregation induced by collagen and fibrinogen (p>0,01), an effect related mainly to the C-terminal and N-terminal domain respectively. Finally, exogenous administration of hrPTX3 reverted the pro-thrombotic phenotype in PTX3 KO mice and improves the outcomes in WT (p<0.01). In conclusion, PTX3 deficiency is associated with increased arterial thrombosis via modulation of collagen and fibrinogen thrombogenicity. In parallel, we investigated the role of PTX3 in the immune-inflammatory response associated to obesity and metabolic disorders, a condition deeply associated with the incidence of cardiovascular events. After 20 weeks of high fat diet (HFD,45% of calories from fat), PTX3 KO mice compared to WT, showed a decreased weight gain (p<0.05), coupled to a decreased accumulation of fat at both 10 and 20 weeks in the visceral (VAT,p<0.05) and subcutaneous adipose depots (SCAT,p<0.05) measured by magnetic resonance for imaging. Basal glycaemia at both 10 and 20 weeks was similar between groups as well as glucose and insulin tolerance measured by glucose (GTT) and insulin tolerance test (ITT), excluding a direct role of PTX3 on glucose homeostasis. As PTX3 is a key component of innate immunity, we focused our attention on the inflammatory response in VAT of PTX3 KO: adipocyte size was significantly smaller (p<0.01) and associated with a decreased infiltration of leukocytes and expression of pro-inflammatory cytokines (MCP-1, IL-6, p<0.05) compared to WT. These data show that deficiency of PTX3 results in reduced HDF-induced obesity as a consequence of a decreased inflammatory state of PTX3 KO VAT. Concluding, we have shown the dual role of PTX3 which plays a protective role in arterial thrombosis, while in a model of diet-induced obesity is associated with the promotion of inflammation and fat deposition in adipose tissue. This dual role suggests that PTX3 may play different functions depending on the origin and the site of action.

Metabolic rate and the proportion of carbohydrate, fat and protein oxidised at rest and during exercise were established in lean large eaters consuming 12843 + 1888 kJ per day and lean small eaters consuming 7090 +1568 kJ per day. Ther average resting metabolic rate in the lean large eaters was 330 + 47 ml oxygen/min. and in the lean small eaters was 285 + 54 ml oxygen/min. The average exercise metabolic rate in the lean large eaters was 1269 + 94 ml oxygen/min and in the lean small eaters was 1253 + 102 ml oxygen/min. In another group of lean large and small eaters, the average post prandial metabolic rate in lean large eaters consuming on average 13875 + 1562 kJ/day was 314 + 45 ml oxygen/min and in lean small eaters consuming 6372 + 1691 kJ/day was 278 + 40 ml oxygen/min. 24 hr energy expenditure in lean large eaters consuming on average 13005 ± 2004 kJ/day was 10191 + 34 kJ/day, and in lean small eaters consuming on average 7529 + 2228 kJ/day was 7156 + 461 kJ/day. However, none of these differences were statistically significant because of wide individual variation and the relatively small number of subjects. The adaptation of metabolic rate to a restricted energy intake was investigated in a group of obese women and a group of obese diabetic women. In the obese women, low metabolic rate observed during food restriction was associated with low nitrogen excretion. Long term metabolic rate measurements (up to 17 weeks) in the obese women who had lost weight indicated that metabolic rate was restored to previous values once feeding had commenced. Clinical studies indicated weight loss was achieved in the obese women without any damage to their health and there was a lowering of blood glucose levels in the obese diabetic women. A survey of 855 very low calorie diet (VLCD) users with relatively little clinical contact but helped by lay personnel confirmed the earlier clinical study that weight loss can readily be achieved by using a VLCD and that weight maintenance for up to a year was good probably because of the improved dietary behaviour as reported by the dieters. The proportion of dieters suffering from side-effects, such as halitosis, postural hypotension, constipation, weakness, hunger and headache were established, these sideeffects were not regarded as serious by most dieters. 88% claimed to feel well while on the diet and 71% claimed an Improvement in their health, while 2.8% consulted their doctor for symptoms which arose while they were on the diet.

Thesis (Ph.D.)--East Carolina University, 2009.
Presented to the faculty of the Department of Exercise and Sports Science. Advisor: Joseph A. Houmard. Title from PDF t.p. (viewed Apr. 30, 2010). Includes bibliographical references.

Obesity, especially if associated with metabolic syndrome, promotes oxidative stress, a low grade chronic inflammatory state, and modify the composition and function of plasma lipoproteins. Oxidative damage to lipoproteins not only make LDL atherogenic but can also alter HDL reducing their anti-atherogenic properties. The possibility of monitoring the lipid peroxidation of the individual regions of LDL and HDL could lead to more detailed information on the molecular mechanisms that are the basis of the increased risk of cardiovascular diseases observed in obesity and metabolic syndrome. The object of this study was to investigate the susceptibility to peroxidation of plasma and of the hydrophobic core and the surrounding envelope of LDL and HDL in obese male (BMI between 25 and 35 Kg mq) with (SM, n=20)) or without (OB, n =40) metabolic syndrome. The susceptibility of plasma to peroxidation was higher in SM and OB than in normo-weight controls (CT, n=60), but not significant differences were observed between these two obese groups. Also the susceptibility to peroxidation of isolated LDL and HDL was higher in both obese groups than in CT. LDL and HDL in SM presented an higher content of triacylglicerols than the corresponding HDL of OB. Moreover, the hydrophobic core of HDL showed a risk of peroxidation significantly higher in SM than in OB. This last parameter was inversely correlated with the waist to hip ratio, an index of visceral obesity. This last evidence seems to indicate that the increase of inflammation typical of the visceral adipose tissue could be one of the major causes of the higher susceptibility to peroxidation found in the hydrophobic core of HDL. The evaluation of the susceptibility to peroxidation of the core and the envelope of LDL and HDL might contribute to the identification of a subset of patients at increased risk of metabolic and cardiovascular complications. Future “ad hoc” randomized clinical trials should be designed to address the effects of weight reduction and /or different diet and/or nutritional supplementation on these parameters.

Several intemet sites sucp as 'Live Well' run by the National Health Service of the United Kingdom promote a 'healthy lifestyle' among citizens by providing information on how to avoid weight gain. A common recommendation to achieve and maintain a 'healthy' body weight is to balance body metabolism. That is, the energy we put in our body (calories we eat) must be the same as the energy we spend (physical activity). This thesis questions the universality of this recommendation and explores the complexity of balancing metabolism in daily life. In order to tackle this issue, this dissertation is premised by posthuman Science, Technology and Society studies (STS). This implies understanding metabolic balance as a set of practices that involve the association of human and non-humans actors. An attention to everyday practices is the guiding principle as this dissertation locates a study of metabolic balance in a case study of how people who suffer from morbid obesity live with bariatric surgery. Empirically this thesis demonstrates that in practice metabolism needs to be continuously re-balanced in daily life to avoid weight (re )gain. I suggest that the process of balancing metabolism may include sets of practices which are beyond the decision making of an informed individual. Metabolic balance, in the case of bariatric surgery, is shared work, an effect of collaborative work by the collective of cure (' healthy' lifestyle recommendations) and secondary care practices (coping with aspects of embodied living such as eating, masticating, drinking, buying, digesting or exercising). Theoretically, it argues that when metabolic balance after a gastric bypass is achieved, it is an effect of tinkering with secondary care practices of body metabolism. Thus, instead of putting big efforts into patient's adherence to a set of general healthy lifestyle recommendations, more attention should be given to care practices which (im)balance metabolism.

Thesis (Ph. D.) University of Missouri-Columbia, 2006.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on July 31, 2007) Includes bibliographical references.

La obesitat y la síndrome metabòlica (SMet) són una de les principals causes de mortalitat arreu del món. L’índex glucémic (IG) i la càrrega glucémica (CG) han estat associades a un augment del risc de desenvolupar obesitat, diabetis tipus 2, SMet i malalties cardiovasculars. Actualment la evidència científica suggereix possibles beneficis de l’IG/CG per a la prevenció i tractament de la obesitat i la SMet. El nostre objectiu va ser analitzar la associació entre IG/CG de la dieta i el risc de desenvolupar SMet i els seus components, a més a més de analitzar la relació entre l’IG/CG i marcadors d’inflamació perifèrics. Per altra banda, vam analitzar la efectivitat d’una dieta de alt IG/CG contra una dieta baixa amb IG/CG i una dieta baixa en greix sobre la pèrdua de pes i la millora del perfil metabòlic, a través de la modulació d’uns mecanismes relacionats amb la sacietat, la inflamació i altres marcadors metabòlics. Aquesta tesi ha estat realitzada en el marc de l’estudi PREDIMED, un assaig clínic nutricional, multicèntric i aleatoritzat; i de l’estudi GLYNDIET, un assaig clínic en paral•lel, aleatoritzat i controlat de 6 mesos de duració. Els resultats obtinguts mostren com les dietes amb alt IG/CG podrien jugar un paper important en el desenvolupament de la SMet i alguns dels seus components. A més, el consum d’aquestes dietes també podria modular alguns marcadors cardiometabolics que contribuirien al guany de pes i al desenvolupament de malalties cardiovasculars. Finalment, vam observar com el consum d’una dieta amb baix IG i un moderat contingut de carbohidrats era més efectiva per la pèrdua de pes i la millora de la sensibilitat i resistència a la insulina que una dieta de alt IG i un moderat contingut de carbohidrats o una dieta baix en greix.
La obesidad y el síndrome metabólico (SMet) son una de las principales causas de la mortalidad a nivel mundial. El índice glucémico (IG) i la carga glucémica (CG) han estado asociados a un mayor riesgo de obesidad, diabetes tipo 2, SMet y enfermedades cardiovasculares. Actualmente la evidencia científica sugiere posibles beneficios del IG/CG para la prevención y tratamiento de la obesidad y SMet. Nuestro objetivo fue analizar la asociación entre el IG/CG de la dieta y el riesgo de desarrollar SMet i sus componentes, además de analizar la relación del IG/CG y marcadores de inflamación periféricos. Por otro lado, analizamos la efectividad de una dieta de alto IG/CG contra una dieta baja en IG/CG y una dieta baja en grasa sobre la pérdida de peso i la mejora del perfil metabólico, a través de la modulación de mecanismos relacionados con la saciedad, la inflamación y otros marcadores metabólicos. Esta tesis se ha realizado dentro del marco del estudio PREDIMED, una ensayo clínico nutricional, multicéntrico i aleatorizado; y el estudio GLYNDIET, un ensayo clínico en paralelo, aleatorizado y controlado de 6 meses de duración. Los resultados obtenidos muestran como las dietas de alto IG/CG podrían jugar un papel importante en el desarrollo del SMet y alguno de sus componentes. Además, el consumo de estas dietas también podría modular algunos marcadores cardiometabólicos que contribuyen a la ganancia de peso y al desarrollo de enfermedades cardiovasculares. Finalmente, observamos como el consumo de una dieta de bajo IG y una moderada cantidad de carbohidratos era más efectiva para la pérdida de peso y la mejora de la sensibilidad y la resistencia a la insulina que una dieta de alto IG y una moderada cantidad de carbohidratos o una dieta baja en grasa.
Obesity and Metabolic Syndrome (MetS) are one of the main causes of disability and death worldwide. It has been proposed that high glycemic index (GI) and high glycemic load (GL) diets are associated with increased risks of obesity, type 2 diabetes mellitus, MetS and cardiovascular disease. To date, evidence suggests possible benefits of the GI/GL for the prevention and management of obesity and MetS. We aimed to analyze the association between dietary GI and GL and the risk of to develop MetS and its features, as well as, the relationship between dietary GI and GL, peripheral adipokines and inflammatory markers. Also, we aimed to analyze the effectiveness of a high GI/GL diet versus a low-GI/GL and a low-fat diet in body weight loss and the improvement of metabolic profile, through the modulation of some mechanisms related to satiety, inflammation and other metabolic risk markers. This thesis has been conducted in the framework of the PREDIMED Study, multicenter randomized nutrition trial, and the GLYNDIET study, a 6-month randomized, parallel, controlled clinical trial. Our results suggest that high dietary GI and GL have a potential role in the development of MetS and some of its components. The consumption of diets with high-GI foods or high dietary GL may also modulate some cardiometabolic markers thus contributing to weight gain and cardiovascular disease. Finally, we found that a moderate-CH low-GI diet may be more effective for weight loss than a moderate-CH high-GI diet or a conventional low-fat diet. The metabolic benefits observed for insulin resistance and sensitivity in those subjects following a low-GI diet, and the tendency to improve other inflammatory and associated metabolic risk markers, also indicate that low-GI diets are better tools for managing obesity and its associated comorbidities.

Abstract Ghrelin is a peptide hormone with anabolic functions. It increases growth hormone secretion and appetite, decreases fat utilisation as a metabolic fuel and increases fat storage in the adipose tissue. In addition, ghrelin exerts effects on glucose metabolism, heart function and inflammatory processes. Due to these characteristics ghrelin has become a hot topic for research focusing on obesity and its co-morbidities such as hypertension, type 2 diabetes and atherosclerosis. The aims of this study were to detect new sequential variations in the genes coding for the ghrelin receptor and ghrelin and to study whether these variations associate with obesity and metabolic risk factors for atherosclerosis. The roles of genetic and environmental factors in the determination of plasma ghrelin levels were also examined. In addition, the association of plasma ghrelin concentrations with disordered glucose regulation and type 2 diabetes was assessed in a longitudinal study. Five single nucleotide polymorphisms (SNPs) in the exons of the ghrelin receptor and 11 SNPs in the ghrelin gene 5´flanking area were found. The SNPs in the ghrelin receptor gene did not associate with plasma IGF-1 concentrations, but two of them did reveal an association with insulin and/or lipid metabolism related parameters. The SNPs found in the ghrelin gene 5´flanking area did not associate with plasma ghrelin levels, but one of them associated with body mass index (BMI). In monozygotic twins discordant for obesity, ghrelin levels were higher in the lean compared with the obese co-twins. Serum ghrelin levels at baseline did not differ between those who maintained normal glucose tolerance and those who developed impaired glucose regulation or type 2 diabetes during the follow up. In conclusion, the results suggest that two variations in the ghrelin receptor gene might be associated with glucose and lipid metabolism but not with IGF-1 levels. One SNP in the ghrelin gene might be associated with obesity. The results also indicate that plasma ghrelin levels are influenced by acquired obesity rather than genetic determinants. Finally, fasting serum ghrelin concentrations do not seem to have a significant predictive value on the incidence of impaired glucose tolerance and type 2 diabetes
Tiivistelmä Greliini on peptidihormoni, jolla on osoitettu olevan anabolisia vaikutuksia. Se voimistaa kasvuhormonin eritystä, toimii ruokahalua ja ravinnonottoa lisäävänä signaalina, vähentää rasvahappojen käyttöä energian lähteenä ja lisää rasvakudoksen määrää. Lisäksi greliinillä on osoitettu olevan vaikutuksia sokeriaineenvaihduntaan, sydämen toimintaan ja tulehduksellisiin prosesseihin. Näiden ominaisuuksiensa ansiosta greliinistä on tullut tärkeä tutkimuskohde lihavuuteen ja sen liitännäissairauksiin, kuten verenpainetautiin, tyypin 2 diabetekseen ja ateroskleroosiin liittyvässä tutkimuksessa. Tässä väitöskirjatutkimuksessa oli tavoitteina etsiä uusia geneettisiä poikkeamia greliiniä ja greliinireseptoria koodaavista geeneistä ja tutkia löytyneiden poikkeamien kytkeytymistä lihavuuteen sekä ateroskleroosin aineenvaihdunnallisiin riskitekijöihin. Tavoitteina oli myös selvittää geneettisten- ja ympäristötekijöiden roolia greliinipitoisuuksien säätelyssä. Lisäksi greliinipitoisuuksien yhteyttä tyypin 2 diabetekseen ja sokeriaineenvaihdunnan häiriöihin tutkittiin seurantatutkimuksessa. Greliinireseptorin geenin eksoneista löytyi viisi ja greliinigeenin 5´reunustavilta alueilta yksitoista yhden nukleotidin geneettistä poikkeamaa. Löytyneillä greliinireseptorin geenin poikkeamilla ei havaittu olevan yhteyttä plasman IGF-1 pitoisuuksiin, mutta kahdella niistä oli yhteyttä insuliini- ja/tai lipidiaineenvaihduntaan liittyviin muuttujiin. Greliinigeenin 5´reunustavan alueen geneettiset poikkeamat eivät liittyneet plasman greliinipitoisuuksiin, mutta yhdellä variaatiolla oli yhteyttä kehon painoindeksiin. Kaksostutkimukimuksissa greliinipitoisuudet olivat korkeammat hoikilla kaksosilla verrattuna lihaviin kaksospareihinsa, huolimatta samasta geeniperimästä. Seurantatutkimuksen alussa mitatut seerumin greliinipitoisuudet eivät ennustaneet tyypin 2 diabeteksen tai muun sokeriaineenvaihdunnan häiriön ilmaantumista. Yhteenvetona voidaan sanoa, että tutkimuksessa löytyneet greliinireseptorin geneettiset poikkeamat saattavat liittyä sokeri- ja rasva-aineenvaihduntaan, mutta eivät niinkään muihin tunnettuihin ateroskleroosin riskitekijöihin. Yksi greliinigeenin variaatioista näyttäisi liittyvän lihavuuteen. Tutkimukset osoittavat, että geneettiset tekijät säätelisivät plasman greliinipitoisuutta vähemmän kuin hankittu lihavuus. Lisäksi serumin greliinipitoisuuksilla ei ole merkittävää ennusteellista arvoa tyypin 2 diabeteksen ilmaantuvuuden suhteen

I investigated genetic and epigenetic variants underlying obesity and related metabolic disturbances with the aim of identifying new disease mechanisms. I first examined the contribution of genetic variation to the increased risk of central obesity (waist-hip-ratio, WHR) in South Asians compared to Europeans by: i) genome-wide association in 10,318 South Asians; ii) exome-wide association in 2,637 South Asians; iii) comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in South Asians and Europeans. I found no associations between population-specific or cosmopolitan SNPs and WHR, and no evidence of larger genetic effects at known WHR loci in South Asians. I next investigated the cell lineages and causal pathways underlying DNA methylation markers associated with BMI in blood (187 loci, P < 1x10-7) by: i. replication testing the loci in isolated white blood cells and adipocytes from obese cases and controls; ii. analysing the relationships between methylation, adiposity, and metabolic disturbances using genetic association. I showed that DNA methylation in blood reflects methylation in isolated white cells (enrichment P < 1.2x10-9) and adipocytes (enrichment P < 0.05), and is predominantly a consequence rather than a cause of adiposity. I finally evaluated genome-wide DNA methylation in isolated subcutaneous and visceral adipocytes from 24 morbidly obese cases and 24 controls (Illumina-450K) to identify putative obesogenic and diabetogenic processes. I discovered widespread differences in DNA methylation between: i. cases and controls (140 loci, P < 1x10-7); ii. subcutaneous and visceral adipocytes (671 loci, P < 1x10-7). Loci were enriched in multiple cellular/molecular pathways (case-control N=47, subcutaneous-visceral N=84, P < 0.001), and identified known obesity and metabolic genes (e.g. IRX3/IRX5, TBX15, PRMD16). These discoveries will be replicated and functionally characterised in future work. Overall, my results suggest that DNA methylation in adipocytes may be important in obesity and metabolic disease pathogenesis, and that methylation in blood may serve as a biomarker of tissue-specific pathobiological processes.

Growing evidence exists for an association between fetal and early growth restriction and the subsequent development of various adult degenerative diseases such as type 2 diabetes and the insulin resistance syndrome. At highest risk are those individuals that were growth restricted in very early life but are obese in adult life. These factors have been addressed in the thrifty phenotype hypothesis. Central to this theory is that the malnourished fetus adapts its metabolism to aid short- and long-term survival but that this adaptation becomes detrimental to health later in life with adequate or overnutrition. The work described in this thesis attempted to model and test the thrifty phenotype hypothesis in the rat. Any role that the deposition of pancreatic amyloid, the most characteristic pancreatic lesion in individuals with type 2 diabetes, may have in the pathogenesis of type 2 diabetes through a thrifty phenotype was investigated by using rats which were transgenic for human amylin (the equivalent native peptide in the rat not precipitating as pancreatic amyloid). Initially a new immunoenzymometric assay for amylin was investigated. Monoclonal antibodies used in this assay were then labelled with eu ropium to establish new sensitive time resolved fluorescence immunoassays for rat amylin and human amylin-like peptides. These assays were used to characterise the human amylin transgenic rats. As well as being genotypically transgenic for human amylin, these rats were shown to make and secrete human amylin in concentrations which are broadly equivalent to concentrations seen in the plasma of individuals with type 2 diabetes. Of all the organs studied the pancreata of the transgenic rats were shown to have the highest human amylin contents. In modelling and testing the thrifty phenotype hypothesis fetal and early growth restriction was achieved by feeding a low protein diet to a pregnant rat and her offspring. At this stage the offspring had better glucose tolerances than equivalent control rats. The low protein offspring became obese in adult life by feeding them a cafeteria-style highly palatable diet. Up to twelve months of age obese rats had worse glucose tolerances than non-obese rats but there was no apparent effect of early growth restriction. Both early growth retardation due to protein restriction and obesity were associated with hypertension at this age. These associations were independent and additive. Between twelve and sixteen months of age there was a relative worsening of glucose tolerance in the low protein, early growth restricted rats. Impaired glucose tolerance was also still evident in obese rats in comparison to non-obese rats. Although the low protein rats had impaired glucose tolerance and were hypertensive they were not hyperlipidaemic. Obese rats, in contrast, were hyperlipidaemic. No pancreatic amyloid deposition was found in any of the rats. In summary, the low protein rat model with dietary-induced obesity exhibits a number of metabolic alterations which are consistent with changes pertaining to the thrifty phenotype hypothesis.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in Western Societies. The pathological processes and risk factors associated with its development begin in childhood, long before clinical consequences emerge. Cardiovascular risk factors have been shown to cluster together in adults and children, particularly in the presence of obesity. Exposure to these risk factors in the first decade of life has been shown to cause vascular endothelial dysfunction and autopsy documented atherosclerosis. Childhood overweight and obesity is increasing in worldwide, Western populations and is strongly associated with vascular dysfunction and arterial stiffness. The aim of this research program was to collect anthropometrical, haematological and physiological data from a large number of apparently healthy Welsh children and adolescents with the purpose of examining central and peripheral haemodynamic indices of arterial stiffness and their association with CVD risk factors. In addition it sought to examine the prevalence of overweight and obesity, the prevalence of metabolic syndrome and examine relationships with emerging risk factors. This study has shown that the prevalence of overweight and obesity in children and adolescents is high yet varies greatly dependent on the measurement methods and cut-off criteria applied. Prevalence estimates for metabolic syndrome ranged from 0% to 3.5%. All measures of adiposity showed significant associations with insulin resistance and with 2 or more components of the metabolic syndrome. Aortic pulse wave velocity increased with increasing BMI status. A negative association was found between arterial stiffness and aerobic fitness. The overall prevalence of hypertension was 9.8% with 4.4% of individuals identified with isolated systolic hypertension. The mechanisms underlying isolated systolic hypertension could not be confirmed through this study. Elevations in alanine aminotransferase were highly prevalent and strongly associated with insulin resistance, fasting insulin, body composition, clustering of metabolic risk factors and inversely related to aerobic fitness.

Thesis (M.Ph.)--Georgia State University, 2008.
Title from file title page. Ike Okosun, committee chair; Richard Rothenberg, Rodney Lyn, committee members. Electronic text (73 p.) : digital, PDF file. Description based on contents viewed November 25, 2008. Includes bibliographical references (p. 69-73).

Metabolic syndrome (MetS) is a condition that is linked to the increased risk of developing chronic diseases, including type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). The association between MetS and chronic disease development lies in the cardiometabolic risk factors that comprise MetS: abdominal obesity, hypertension, hyperglycaemia and dyslipidaemia [1]. The development of MetS is also associated with the dysregulation of many different body systems, such as the immune system [2] and gut microbiome [3]. Due to its multifactorial nature, research in MetS requires the simultaneous analysis of multiple biomarkers across different body systems. As most research thus far have utilised univariate analysis, no biomarker profile has been identified to characterise individuals more at risk of MetS and related diseases. The current study has therefore implemented the use of correlationbased network analysis (CNA) and multiple classification models to identify the biomarkers that collectively link to increased MetS development. Four variable groups comprising of multiple different measurements were obtained from 117 healthy weight controls and 35 obese with MetS individuals. The four variable groups consisted of: anthropometric measures, haematological measures, gene expression levels and gut microbial counts. The use of CNA allowed a better understanding of the relationships between biomarkers affected by MetS. As expected, the obese with MetS network was denser than the healthy weight control network, demonstrating the complex nature of MetS. The results found molecular interactions supporting the findings of previous literature, particularly correlations that demonstrated the development of anaemia of inflammation in the obese with MetS network. There were also three key hubs identified using gene expression levels, involving transcription factor EB (TFEB), lipocalin 2 (LCN2), and cluster of differentiation- (CD-) 68. The three genes are associated with regulatory T cells and neutrophils, two prominent cells in regulating the inflammatory state. As obesity and MetS are often described as a state of chronic low-grade inflammation, the findings of CNA correspond with that of previous studies. Classification models are another type of analytical tool that have demonstrated high predictive ability in many diseases, including T2DM and CVD. The use of classification models for the prediction of diseases allows the risk of disease development to be evaluated. The current study applied classification models for the prediction of MetS using three of the four variable groups measured: haematological measures, gene expression levels and gut microbial counts. Classification models are not only able to assess the relevance of these variable groups to MetS but also identify the specific variables that contributed the most to MetS development. There are a range of classification models that can be used and due to MetS being a relatively new area of research, the most appropriate model for MetS prediction has yet to be determined. As such, the current study predicted MetS using four different types of classification models and compared the predictive abilities of each model. The four models that were used in the current study were: logistic regression (LR), decision tree (DT), support vector machine (SVM) and artificial neural network (ANN). The performance of each classification model was evaluated using 10-fold cross-validation, which splits the dataset into 10 training and testing sets. Each model is then built using the training sets and evaluated using the testing sets to ensure that the model was not fit too closely to the training data. The model with the highest performance when predicting MetS using haematological measures and gut microbial counts was ANN, while SVM had the highest performance when using gene expression levels. However, ANN was also able to attain a high area under the curve (AUC) value of 0.804 when predicting MetS using gene expression levels. As such, the prediction model that had the highest performance overall was ANN. Each model has their own strengths and limitations dealing with specific types of data and the most appropriate model depends on the research question being asked. Although SVM and ANN are both very powerful algorithms, capable of handling high-dimensional data, both models have difficulty producing clinically significant results. On the other hand, LR and DT models are both able to identify specific biomarkers that should be further investigated for links to diseases development, deeming them more suitable for clinical applications. For each of the 10 LR and DT models, constructed using the 10 training sets, the haematological measurement that was found to be most important was triglycerides (TG). Additionally, the best performing LR model, out of the 10 constructed models, found measurements of TG, platelets (PLT), erythrocyte sedimentation rate (ESR), fasting plasma glucose (FPG), haemoglobin (HG) and glycated haemoglobin A1c (HbA1c) to be associated with MetS development. At the same time, high-density lipoprotein-cholesterol (HDL-C) was linked to a reduced risk of MetS development. Using DT, the important measurements in MetS development were TG, PLT, HDL-C, age, HG, C-reactive protein (CRP) and white cell counts. Each variable identified has been found to be linked to either a cardiometabolic risk factor or inflammation and thus the results of the current study are supportive of previous literature on obesity and MetS. Logistic regression also found the expression of AKT serine/threonine kinase 3 (AKT3), Fc fragment of IgE receptor II (FCER2), cathelicidin antimicrobial peptide (CAMP), interleukin- 11 receptor subunit alpha (IL11RA) and granzyme H (GZMH) to increase the odds of developing MetS while C-X-C motif chemokine receptor 6 (CXCR6), C-C motif chemokine ligand- (CCL-)3, suppressor of cytokine signalling 1 (SOCS1) and killer cell lectin like receptor C2 (KLRC2) expression reduces these odds. Consistent with these findings, DTs also predicted individuals with high AKT3, FCER2 and CAMP expression to be obese with MetS while healthy weight controls had higher CXCR6, CCL3 and KLRC2 expression. The findings of the current study were partially supportive of previous literature, with FCER2 and CAMP expression being associated with obesity and inflammation [4, 5] and KLRC2 expression being inversely associated with obesity and inflammation [6, 7]. On the other hand, AKT3 is associated with glucose and lipid metabolism [8] with evidence of its expression leading to the protection against insulin resistance. As such, the high AKT3 expression found in the obese with MetS cohort was not consistent with current literature. Similarly, the association between the expression of CXCR6 and CCL3 with a healthy weight control classification could not be explained as both genes are typically linked to inflammation [9, 10]. Finally, LR and DT found microbial species belonging to the Firmicutes and Bacteroidetes phyla to both be associated with the increased and reduced risk of developing obesity with MetS. Obesity with MetS is largely characterised by a high Firmicutes-to-Bacteroidetes ratio, particularly when compared to healthy weight controls [11]. While this pattern was not clearly evident in the current study, the cause of discrepancy with previous literature may be due to gut microbial studies in obesity and MetS not being typically reported at the species level. While LR and DT are both able to identify the variables that are likely to contribute to MetS development in a clinical setting, the performances of either model were not able to compete with that of ANN or SVM. At the same time, despite having the highest performance overall, ANN is unable to produce easily interpretable results with clinical significance. As such, its high predictive ability is not enough to convince researchers to choose ANN for clinical use. To overcome this issue, many researchers combine ANN with a feature selection technique, such as genetic algorithm (GA). Feature selection techniques are able to identify the best combination of biomarkers for the prediction of diseases. In the current study, the variables that were recognised to be significant by the hybrid model supported the findings of LR and DT. The haematological biomarkers that were consistently recognised as important by all three prediction models were measures of TG and HG. Additionally, CCL3 and CXCR6 expression, as well as three gut microbial species belonging to the Firmicutes and Bacteroidetes phyla, were also found to be important for MetS development. Other than the identification of important variables, the hybrid model was also able to improve the performance of ANN when predicting MetS using gene expression levels and gut microbial counts. Consequently, the current study concluded that the hybrid GA with ANN model was considered to be the most appropriate for MetS prediction. Another analytical method that was used by the current study was weighted majority voting, which combines the final predicted outcomes of the other classification models to determine whether the performance could be further improved. The weighted majority voting method was able to achieve the highest AUC value for the prediction of MetS using gut microbial counts as well as the second highest AUC when using haematological measures and gene expression levels. However, the dependency of the weighted majority voting method on the performance of individual classification models used was demonstrated in the study. The low sensitivity values attained by DT in the testing set of all three variable groups is likely what prevented the weighted majority voting method from outperforming all the other classification models in the prediction of MetS. In spite of the limitation caused by DT, however, the method was still able to achieve a high performance. As such, the combination of the results from different classification models into a weighted majority voting method to increase the overall predictive ability was found to be a viable choice. The classification model that was found to be most suitable for the prediction of MetS was the hybrid GA with ANN model. Not only was the model able to achieve high predictive ability due to the ANN portion of the model, it was also able to reveal the optimal combination of variables that contributed the most to an accurate MetS prediction. The variables that were identified were also supportive of the findings of both LR and DT. The measurements used by the current study (haematological measures, gene expression levels and gut microbial counts) were all found to be suitable for the prediction of MetS. Future studies may consider the use of other biomarkers, including measurements from adipose tissue, for the prediction of MetS using the hybrid GA with ANN model.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Novel approaches are required to address Alzheimer’s disease (AD) in our ageing population, with recent interest focused on inflammation and oxidative stress (OS). Disruption of NF-E2-related factor 2 (Nrf2) signalling increases OS and promotes AD. Amyloid precursor protein (APP) is intimately linked with AD, with the Swedish mutation (hAPP_swe) used in numerous transgenic models. Furthermore, increasing importance has been placed on the suggested link between nutritional status and AD. To assess Nrf2 as a potential target in AD, we examined the effect of metabolic stress, by chronic high fat (HF) feeding or acute lipopolysaccharide (LPS) treatment on the brains of aged WT, Nrf2^-/-, hAPPswe and Nrf2^-/-/hAPP_swe mice.  Nrf2^-/- mice displayed impaired enthorinal cortex-dependent cognition, with raised basal hippocampal inflammation. The inflammatory state was attenuated by chronic HF feeding, whilst maintaining insulin sensitivity. In contrast, hAPP_swe did not display an inflammatory response to HF feeding, but demonstrated impaired insulin signalling; in line with AD-associated insulin resistance. Additionally, Nrf2^-/- mice display increased glial cell activation and activation of mitogen activated protein kinases and mitochondrial impairment. These may be indicative of OS-induced cellular dysfunction and is supported by an aggravated response to LPS, which potentiates IL-1β production. Furthermore, despite an attenuated LPS response following the induction of tolerance, Nrf2^-/- mice maintain glial cell activation following treatment which may be suggestive of a primed immune environment within the brain.  In conclusion, these data indicate altered glucose homeostasis in both Nrf2^-/- and hAPP_swe mice, as previously reported. Further, we advocate that Nrf2 plays a key role in mitochondrial function and health and may be important for the ameliorative effects of HF feeding. Taken together, mitochondrial dysregulation and associated OS may help explain the development of cognitive impairment in Nrf2^-/- mice. This may be relevant for AD given the age-dependent decline in Nrf2 expression in humans.