Dissertations / Theses on the topic 'Syndromic obesity'

Obesity hypoventilation syndrome (OHS) represents the most severe form of sleep disordered breathing occurring in obese individuals and results in hypoventilation, both during sleep and in wakefulness. OHS is associated with significant morbidity and increased health, social and economic burdens for the individual and health care system. Mortality in OHS has been shown to be significantly higher than in individuals with eucapnic obstructive sleep apnoea (OSA), even when effective treatment with positive airway pressure (PAP) therapy has been established. In these individuals, it is cardiovascular disease rather than respiratory failure, which is the most common cause of death. The work presented in this thesis focuses on 3 aspects of OHS: development of a predictive model for early identification of obese patients with nocturnal-only hypoventilation, thought to represent an earlier stage of OHS; comparison of neurocognitive function pre and post PAP therapy in OHS and equally obese individuals with OSA; and the impact of PAP therapy on cardio-metabolic and renal biomarkers in OHS patients, comparing this with equally obese individuals with OSA.

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.

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.<br>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.<br>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.

There is a frequent concurrence of obesity and polycystic ovary syndrome (PCOS). To confirm the mechanistic link between these two common conditions, the studies detailed in this thesis have employed both genetic and physiological approaches.

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.

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.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Medical Science<br>Griffith Health<br>Full Text

An animal model to study complications resulting from childhood obesity is lacking. Our objective was to develop a porcine model for studying mechanisms underlying diet-induced childhood obesity. Pre-pubertal female pigs, age 35 d, were fed a high-energy diet (HED; n = 12), containing tallow and refined sugars, or a control corn-based diet (n = 11) for 16 wk. Initially, HED pigs self-regulated energy intake similar to controls, but, by wk 5, consumed more (P < 0.001) energy per kg body weight. At wk 15 and 22, pigs were subjected to an oral glucose tolerance test (OGTT); blood glucose increased (P < 0.05) in control pigs and returned to baseline levels within 60 min. HED pigs were hyperglycemic at time 0, and blood glucose did not return to baseline (P = 0.01), even 3 h post-challenge. During OGTT, glucose area under the curve was higher and insulin area under the curve was lower in HED pigs compared to controls (P = 0.001). Pigs given 6 wk of dietary intervention, consuming a control diet, marginally improved glucose area under the curve and LDL-cholesterol although insulin area under the curve was unaffected. Chronic HED intake increased (P < 0.05) subcutaneous, intramuscular, and perirenal fat deposition, and induced hyperglycemia, hypoinsulinemia, and low-density lipoprotein hypercholesterolemia; however, a 6 wk dietary intervention partially recovered a normal physiology. These data suggest pre-pubertal pigs fed HED are a viable animal model for studying childhood obesity.<br>Master of Science

Smith-Magenis syndrome (SMS) is a complex disorder caused by haploinsufficiency of RAI1 and characterized by sleep disturbances, behavioral abnormalities, mental retardation, and obesity in teens and adults. Rai1+/- mice are obese after 20 weeks. Dup(17)(p11.2) syndrome is a complex disorder associated with overexpression of RAI1. A transgenic mouse model of dup(17)(p11.2) syndrome overexpresses Rai1 and results in a mouse that is growth delayed. In order to characterize the obese phenotypes of mouse models of SMS and the role of RAI1 in obesity, daily food intake and serum levels of insulin, glucose, PPY, and leptin were measured; adiposity was studied by characterizing fat deposition; and gene expression was studied in the hypothalamus. These studies show that Rai1+/- mice are hyperphagic, consume more during the inactive light phase, and have altered satiety genes in the hypothalamus. Adiposity studies have shown WT females have a higher body fat content and visceral fat proportion than males, but Rai1-Tg and Rai1+/- females have similar fat deposition patterns as WT males. Hypothalamic gene expression studies show that many genes and pathways are affected by Rai1 and Rai1 dosage, including many genes associated with obesity and satiety.

Thesis (M.Ph.)--Georgia State University, 2008.<br>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).

Pharmacology<br>Ph.D.<br>The global incidence of overweight and obese individuals has skyrocketed in the past few decades resulting in a new health epidemic. In 1980, 5% of males and 8% of females were categorized as obese; by 2008 these values doubled equating to half a billion adults worldwide. This surge of overweight and obese individuals has driven a dramatic increase in people afflicted with metabolic disorders. As such, the term "metabolic syndrome" (MetS) has been coined to describe several interrelated metabolic risk factors which often present in concert. Specifically, metabolic syndrome refers to the presence of at least three of the following five conditions: central obesity, elevated triglycerides, diminished high density lipoprotein (HDL) cholesterol, hypertension, and insulin resistance (IR). MetS is a major health concern due to its ability to increase the likelihood of cardiovascular disease (CVD), diabetes, and other life-threatening ailments. In light of this growing medical epidemic, we have concentrated our efforts in evaluating the role of microRNA-155 (miR-155) in MetS development. MicroRNAs are a newly defined class of small, non-coding RNA which contain the unique ability to regulate gene expression through RNA interference. As a result of this ability, microRNAs can mediate a wide variety of cellular processes. In order to evaluate the function of miR-155 in MetS, we established a novel miR-155-/-/ApoE-/- (DKO) mouse model. Coupling this model with the use of normal rodent or high fat diets allowed us to investigate how states of caloric balance and surplus affected the manifestation of the individual MetS components. We found that male and female DKO mice fed a high fat diet had significantly augmented body masses of 18% and 10% respectively, when compared to ApoE-/- counterparts on the same diet. Evaluation of this phenotype with body composition analysis revealed an 18% and 46% increase in body fat percentage among the male DKO mice on normal and high fat diets, respectively. This trend was also observed in female DKO mice, albeit to a lesser extent. This phenotype was further substantiated by the observation of augmented gonadal white adipose tissue pad mass within male and female DKO mice fed either chow. This equated to a 43% and 112% increase in male mice and a 45% and 57% augmentation in female mice for normal and high fat chow diets, respectively. In light of our findings, we also evaluated how miR-155 impacted glucose and insulin sensitivity. We found levels of insulin to be augmented by 181% and 148% in male DKO mice on normal and high fat diets, respectively. Furthermore, we found these mice to be euglycemic. These observations suggest that DKO mice are IR but capable of compensating for their insensitivity with elevated insulin production. Due to the tight association between MetS and the development of non-alcoholic fatty liver disease (NAFLD) as well as CVD, we felt it prudent to investigate the manifestation of these conditions. We found elevated hepatic mass of 40% and 13% in male and female DKO mice on high fat chow. Furthermore, hepatic discoloration was seen in these mice prompting us to perform in-depth histological evaluation which revealed widespread steatosis, a hallmark of NAFLD. Meanwhile, investigation of atherosclerosis, the key underlying cause of most CVDs, unexpectantly revealed diminished development. Due to the complex nature of atherosclerosis it is tough to explain the exact reason for this observation. Independent reports have shown that miR-155 plays a critical role in the development, maturation, or activation of B-cell, T-cells, macrophages, and dendritic cells. As a result, decreased immune cell infiltration may be the root cause for the observed decline in atherosclerosis. Taking into account our observations of obesity, IR, and NAFLD in conjunction with independent findings of blood pressure mitigation by miR-155, we feel confident in reporting that miR-155 is a vital factor in preventing MetS and NAFLD development. Despite this, we surprisingly found atherosclerosis development to be diminished in these mice suggesting a pro-inflammatory role in atherogenesis. This duality highlights the complex and ambiguous nature of miRNAs. In light of this, further evaluations should be conducted to gain additional insight into these pathologies and hopefully the development of novel therapeutics.<br>Temple University--Theses

The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM. To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V). Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V). In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.

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

Abstract The polycystic ovary syndrome, described first as the association of bilateral polycystic ovaries and amenorrhoea, oligomenorrhoea, hirsutism and obesity, was later shown to be a complex metabolic syndrome. The first purpose of this study was to investigate the occurrence of hyperinsulinaemia and the severity of insulin resistance and glucose tolerance disorders in polycystic ovary syndrome by means of the oral glucose tolerance test and the euglycaemic hyperinsulinaemic clamp. The next goal was to investigate whether women with polycystic ovary syndrome would benefit from insulin-sensitising drugs, and in particular to compare the effects of metformin and a contraceptive pill containing ethinyl oestradiol and cyproterone acetate. Altogether, 81 women with polycystic ovary syndrome and 34 healthy control subjects were involved in the study. Marked impairment of insulin sensitivity in obese subjects with polycystic ovary syndrome, including a decrease of both cellular oxidative and non-oxidative utilisation of glucose, and a slight non-significant decrease of insulin sensitivity in non-obese subjects was observed. Both non-obese and obese subjects with polycystic ovary syndrome exhibited increased abdominal obesity compared with the controls, confirming the fact that obesity, in particular abdominal obesity, is an important contributor in the development of insulin resistance in this syndrome. Metformin alleviated hyperandrogenism by essentially decreasing ovarian, but not adrenal androgen secretion. The improvement of hyperandrogenism and ovarian function seemed to be mediated by the improvement of hyperinsulinaemia, which resulted itself from subtle improvements in both hepatic insulin extraction and insulin sensitivity. Metformin decreased abdominal obesity and the release of free fatty acids from adipose tissue, and improved ovarian cyclicity and fertility. The transient decrease in serum leptin levels observed may have some role in the improvement of ovarian function. The contraceptive pill significantly improved hyperandrogenism and hirsutism, and it slightly affected glucose metabolism. Thus, it could be the treatment of choice in women with hirsutism problems and no fertility hopes. Metformin could be the drug of choice for women with polycystic ovary syndrome who wish to conceive. Because of its beneficial metabolic effects, the value of metformin in reducing the risk of cardiovascular diseases in polycystic ovary syndrome needs to be further studied.

lean individuals and the impact ofdietary intervention on microbiota, obesity and diet, showed differences in faecal microbiota. Furthermore obese individuals had Molecular characterisation of microbiota and fermentation end-products of lean and obese humans on open recorded diet, and obese humans on saturated fat-rich The human microbiota has recently been implicated in the new obesity metabolic syndrome (MS) biomarkers. epidemic sweeping the world. This thesis explored the gut microbiota of obese and higher faecal short chain fatty acid (SCFA) concentrations (p<0.01, n=13). Additionally, the three groups presented distinct faecal and urine IH-NMR metabolite profiles. C57b16/J mice fed a high fat-diet (HF) for 4 weeks had fewer ceacal Eubacterium rectale/Clostridium coccoides group, Bacteroides-like Mouse Intestinal Bacteria, and Bifidobacterium spp. (p<0.001) compared to standard chow-fed mice. This altered microbiota was concomitant with increased plasma pro-inflammatory cytokine levels, endotoxernia, insulin resistance and obesity. Prebiotic supplementation (oligofructose, 10% wt/wt, 14 weeks) significantly increased caecal bifidobacteria (p<0.001) in HF-fed mice. This was positively correlated with improved MS risk factors. In humans at risk ofMS (n=88), modulating the type and quantity of dietary fat (i.e. saturated vs monounsaturated fat) and carbohydrate (Le. high vs low glycaemic index (GI)) impacted on the gut microbiota. Twenty-four weeks on test diets with increased carbohydrate and reduced fat content, irrespective of dietary GI, increased faecal bifidobacteria (p=O.OOS, p=O.OS2) and decreased fasting glucose (p==O.OlS, p==O.034), total-cholesterol (p=O.032, p==O.023) and LDL-cholesterol (p==O.043, p=O.043). In the high GI group fasting insulin concentrati<?n and body fat percentage decreased (P<O.OS). Diets with higher fat and reduced CHO content decreased total bacteria (p=O.023, p=O.OOS, p==O.102). The saturated fat-rich diet increased faecal concentrations of main SCFA (p<O.OS). This work confirms recent observations implicating the gut microbiota in the biology ofobesity, suggesting that dietary microbiota modulation may be correlated with improved health in obese.

Polycystic ovarian syndrome (PCOS) is a highly prevalent heterogeneous syndrome associated with abdominal obesity, insulin resistance and the metabolic syndrome. This clustering of risk factors could translate into an adverse cardiovascular disease (CVD) risk profile. Endothelial dysfunction, an early barometer of CVD, has been exhibited by women with PCOS; however, it remains unclear whether endothelial dysfunction is independent of CVD risk factors in this population. Exercise training has been found to enhance conduit artery and cutaneous microvessel endothelial function in various populations. Nevertheless, limited research exists regarding the cardiovascular effects of exercise in PCOS, and its impact on endothelial function in conduit arteries and cutaneous microvessels, has not been explored. The primary aim of this thesis was to examine nitric oxide (NO)-mediated endothelial function at different levels of the vascular tree in women with PCOS and to establish whether supervised exercise training induces a therapeutic effect on endothelial function. A systematic review of published studies comparing FMD in PCOS and control women was conducted. Twenty-one published studies were identified for inclusion (pCOS n=908; controls n=566). Differences in FMD between PCOS and controls were synthesised and meta-regressed against BMI and age. The pooled mean FMD was 3.5% lower (95% CI=3.4, 3.7%; P < 0.001) in women with PCOS compared with controls; and the PCOS-mediated reduction in FMD was most evident in studies involving less obese women. PCOS [n=35, 28y (95% CI=26, 30), 31kg/m2 (95% CI=27, 35)] and control women [n=16, 32y (95% CI=30, 35), 30kg/m2 (95% CI=25, 32)] were recruited. Brachial artery endothelial function was assessed using flow-mediated dilation (FMD). Internal adipose tissue (lAT), subcutaneous (SAT), visceral (VAT) and abdominal SAT was quantified using whole body magnetic resonance imaging and IH magnetic resonance spectroscopy quantified liver and skeletal muscle fat. Cardiorespiratory fitness, glycaemic control, reproductive hormone and lipid profiles were also assessed. FMD was impaired in PCOS when compared with control women [-4.5% (95% CI=-6.3, -2.8), P < O.OOl]. When FMD was adjusted for individual differences in IAT [-4.3% (95% CI=-6.l, -2.4), P < O.OOl], VAT [-4.4% (95% CI=-6.3, -2.5), P < O.OOl] and insulin resistance [-3.9% (95% CI=-5.6, -2.1), P < O.OO 1], the difference in FMD between groups remained. Ten women with PCOS [27y (95% CI=23, 32), 31 kg/rrr' (95% CI=28, 34)] completed a 16-week supervised exercise programme while 7 women with PCOS [29y (95% CI=24, 35), 35kg/m2 (95%CI=31, 40)] opted for conventional care and followed simple lifestyle advice. Exercise training improved FMD to a greater degree than conventional care [3.4% (95% CI=1.8, 5.1), P > 0.0005] and in parallel greater improvements in cardiorespiratory fitness were observed with exercise [4.7ml/kg/min (95% CI=1.4, 7.9), P=0.005]. These changes with exercise occurred independently of changes in VAT, SAT or insulin resistance. NO-mediated vasodilation in the cutaneous microvessels was examined in 11 PCOS [29y (95% CI=25, 34), 34kg/m2 (95% CI=30, 38)] and 6 control women [29y (95% CI=21, 37), 34kg/m2 (95% CI=28, 39)] using laser Doppler flowmetry combined with intra-dermal microdialysis of L-NG-monomethyl arginine to assay the NO dilator system in response to incremental local heating of the forearm. Six women with PCOS [30y (95% CI=22, 37), 31kg/m2 (95% CI=25, 37)] then undertook a 16-week exercise-training programme. Nitric oxide contribution was attenuated in women with PCOS at peak heating [-16.0CVCmax (95% CI=-32.5, 0.6), P=0.05] and during prolonged maximal heating [-15.4CVCmax (95% CI=- 29.6, -1.3), P=0.04], compared with control women. Cardiorespiratory fitness improved by 5.0ml/kg/min (95% CI=0.9, 9.2) following exercise training (P=0.03). This was accompanied by increased NO contribution to cutaneous blood flow between 36.5-42°C (P < 0.05), at peak heating [19.6CVCmax (95% CI=4.3, 34.9), P=0.02] and during prolonged maximal heating [17.1CVCmax (95% CI=2.2, 32.2), P=0.03]. The findings from this thesis suggest that endothelial dysfunction is an intrinsic characteristic of PCOS and that supervised exercise training enhances endothelial function in both conduit vessels and cutaneous microvessels, independent of adiposity or traditional CVD risk factors. The direct impact of exercise training on the vasculature of women with PCOS may decrease the risk of CVD morbidities, such as hypertension, and consequently reduce cardiovascular mortality in post-menopausal years.

The primary aims of the thesis were to investigate the respiratory effects of supplemental oxygen (O2) in people with obesity hypoventilation syndrome (OHS), and to investigate the effects of positive airway pressure (PAP) on responses to O2 in people with OHS. In a double-blinded randomised crossover study, 14 participants with stable untreated OHS and 14 age-and gender-matched controls breathed O2 concentrations 28% and 50% each for 20 minutes in random order, separated by a 45-minute washout. OHS participants were then commenced on nocturnal PAP and re-tested after 3 months. Among untreated OHS participants, O2 induced hyperoxia and hypoventilation, leading to rises in arterialised-venous carbon dioxide (PavCO2) of 2.0±1.7 mmHg (28% O2) and 3.7±3.2 mmHg (50% O2) (both p<0.05), and mild acidaemia during 50% O2. In controls, PavCO2 and pH did not change with either O2 concentration. After PAP, OHS participants experienced smaller O2-induced PavCO2 rises of 1.3±2.3 mmHg (28% O2) and 0.9±1.7 mmHg (50% O2), changes which were initially significantly different to responses before PAP, but were non-significant after statistical adjustment. It was concluded that moderate concentration O2 worsens carbon dioxide and pH in people with OHS, and that these responses may be attenuated by PAP. The validity of arterialised-venous blood gas (AVBG) sampling and LifeShirt™ respiratory inductive plethysmography (RIPLS) were also investigated. In the study validating AVBG, 42 paired AVBG and arterial blood samples from OHS and control participants were compared using Bland Altman analysis. It was concluded that AVBG-arterial agreement is acceptable for PavCO2, pH and bicarbonate, allowing this specifically validated tool to be used in the clinical studies. In the study validating RIPLS, it was concluded that RIPLS produces valid measures of respiratory frequency among controls but not OHS participants, and is not valid for quantifying respiratory volumes among either population.

L’obésité est un problème de santé publique à l’échelle mondiale, sa prévalence augmente de façon continue dans l’ensemble des pays et son origine est complexe. Elle résulte de nombreux facteurs parmi lesquels des changements alimentaires et une sédentarité accrue. Elle est associée à un état inflammatoire chronique de faible intensité et à un stress oxydant. De nombreux travaux montrent que le surpoids et l'obésité sont les principales causes de développement de pathologies métaboliques tels que le diabète de type II et la stéatose hépatique, pouvant conduire à une morbidité et une mortalité importantes. La découverte récente d’une classe de lipides bioactifs, les esters d'acides gras et d'acides gras hydroxylés (FAHFAs), ouvre des perspectives prometteuses dans la prévention des désordres métaboliques associés à l’obésité. Les FAHFAs sont synthétisés de façon endogène et sont présents dans de nombreux aliments et il a été montré que les FAHFAs, en particulier les isomères d’acide palmitique estérifié à l’hydroxy acide stéarique (PAHSA), possèdent des effets antidiabétiques et anti-inflammatoires. L’objectif de ce travail de thèse est d’explorer l’impact de FAHFAs jamais étudiés précédemment sur le métabolisme musculaire et/ou hépatique et de vérifier leurs effets antidiabétiques et anti-inflammatoires. Pour répondre à ces objectifs nous avons effectué dans un premier temps des études in vitro sur des myoblastes C2C12 avec onze FAHFAs différents puis nous en avons sélectionné deux sur la base des résultats obtenus in vitro, le 9-PAHPA et le 9-OAHPA, pour tester leurs influences in vivo chez la souris C57Bl6/J. Nous montrons que les onze FAHFAs testés diminuent la prolifération des cellules C2C12, probablement en inhibant l'activité mitochondriale, mais n’ont pas d’effet au cours de la phase de différenciation. Chez les souris ayant reçu un régime contrôle supplémenté en 9-PAHPA ou en 9-OAHPA nous observons dans le muscle squelettique une orientation des chaines lourdes de myosine vers un phénotype contractile plus oxydatif. Le 9-PAHPA et le 9-OAHPA modulent également le métabolisme basal et augmente la sensibilité à l'insuline chez les souris. Cependant, chez certaines souris cette hypersensibilité à l’insuline s’accompagne de lésions hépatiques probablement en raison d’une stimulation de la lipogenèse de novo. Sous régime obésogène, nous retrouvons l’effet insulino-sensibilisant du 9-PAHPA et du 9-OAHPA sans pour autant observer de lésions au niveau du foie. Globalement, l’ensemble de ces résultats démontre que le 9-PAHPA et le 9-OAHPA possèdent des effets intéressants dans la prévention des désordres métaboliques associés à l’obésité. Il met en évidence la complexité d'action des FAHFAs, dont la fonction biologique semble dépendre de leur structure et de leurs tissus cibles<br>Obesity is a global public health problem, its prevalence is increasing continuously in all countries and its origin is complex. It is the result of many factors, including dietary changes and increased inactivity. It is associated with a chronic inflammatory state of low intensity and oxidative stress. Numerous studies show that overweight and obesity are the main causes of the development of metabolic pathologies such as type II diabetes and fatty liver disease, which can lead to significant morbidity and mortality.The recent discovery of a class of bioactive lipids, esters of fatty acids and hydroxylated fatty acids (FAHFAs), opens up promising perspectives in the prevention of metabolic disorders associated with obesity. FAHFAs are synthesized endogenously and are present in many foods and it has been shown that FAHFAs, in particular isomers of palmitic acid esterified with hydroxy stearic acid (PAHSA), have anti-diabetic and anti-inflammatory effects .The objective of this thesis work is to explore the impact of FAHFAs never previously studied on muscle and / or liver metabolism and to verify their antidiabetic and anti-inflammatory effects. To meet these objectives, we first carried out in vitro studies on C2C12 myoblasts with eleven different FAHFAs, then we selected two based on the results obtained in vitro, 9-PAHPA and 9-OAHPA. test their influences in vivo in the C57Bl6 / J mouse.We show that the eleven FAHFAs tested decrease the proliferation of C2C12 cells, probably by inhibiting mitochondrial activity, but have no effect during the differentiation phase. In mice having received a control diet supplemented with 9-PAHPA or 9-OAHPA we observe in skeletal muscle an orientation of the heavy chains of myosin towards a more oxidative contractile phenotype. 9-PAHPA and 9-OAHPA also modulate basal metabolism and increase insulin sensitivity in mice. However, in some mice this hypersensitivity to insulin is accompanied by liver damage probably due to stimulation of de novo lipogenesis. Under obesogenic diet, we find the insulin-sensitizing effect of 9-PAHPA and 9-OAHPA without observing any lesions in the liver.Overall, all of these results demonstrate that 9-PAHPA and 9-OAHPA have interesting effects in the prevention of metabolic disorders associated with obesity. It highlights the complexity of action of FAHFAs, whose biological function seems to depend on their structure and their target tissues

Adipose tissue is a multi-functional organ with metabolic implication far beyond its role in energy storage, therefore its relevance in obesity and consequent metabolic dysregulation has been largely investigated. Ghrelin is a gastric hormone whose circulating levels are predominantly in the unacylated form (UnAG). While the acylated form was first characterized for its important effects on energy balance, UnAG has recently shown to be independently involved in several metabolic functions, including a role as positive modulator of oxidative stress, inflammation and insulin sensitivity in skeletal muscle. However, to date, very little is known about UnAG effects in adipose tissue, another important metabolic organ. The current study proposes to investigate UnAG implications in rodents adipose tissue metabolism by testing 1) 4-day of UnAG sustained exogenous administration on healthy rats and 2) transgenic systemic overexpression of UnAG in mice treated with standard or high-fat diet (HFD). Complexively our results showed that in healthy rodents, UnAG does not modify mitochondrial activity, antioxidant systems and inflammatory state but it decreases insulin sensitivity in both models of UnAG administration or overexpression. Interestingly though, in obese mice UnAG systemic overexpression, the hormone was found to prevent alterations of mitochondrial function and dynamics, redox state and inflammatory response. Consistently, UnAG also improved insulin sensitivity of obese mice, and finally prevented HFD-related adipocytes enlargement with lower actin remodeling. In support of these in vivo results, clinical analyses in humans showed that UnAG circulating levels decrease in elderly overweight-obese individuals compared to lean and are predictive of 5-year mucle mass independently from BMI. Consistently, in a general population cohort fat-to-mass ratio was negatively correlated to UnAG levels, independently from BMI and other metabolic variables. Globally, our findings in animal and human studies suggest UnAG as a novel modulator of adipose tissue metabolism with important implications in obesity pathogenesis, suggesting UnAG as a potential candidate for further studies aiming to contrast obesity and obesity-associated metabolic complications.

BACKGROUND: Among patients with obstructive sleep apnea (OSA) a higher number of medical morbidities are known to be associated with those that have obesity hypoventilation syndrome (OHS) compared to OSA alone. OHS can therefore pose a higher risk of postoperative complications after elective non-cardiac surgery (NCS) and is often unrecognized at the time of surgery. The objective of this study was to retrospectively identify patients with OHS and compare their postoperative outcomes with those who have OSA alone. METHODS: Patients meeting criteria for OHS were identified within a large cohort of patients with OSA who underwent elective NCS at a major tertiary care center. We identified postoperative outcomes associated with OSA and OHS as well as the clinical determinants of OHS (BMI, AHI). Multivariable logistic or linear regression models were used for dichotomous or continuous outcomes, respectively. RESULTS: Patients with hypercapnia from definite or possible OHS, and overlap syndrome are more likely to develop postoperative respiratory failure [OR: 10.9 (95% CI 3.7-32.3), p<0.0001], postoperative heart failure (p<0.0001), prolonged intubation [OR: 5.4 (95% CI 1.9-15.7), p=0.002), postoperative ICU transfer (OR: 3.8 (95% CI 1.7-8.6), p=0.002]; longer ICU (beta coefficient: 0.86; SE: 0.32, p=0.009) and hospital length of stay (beta coefficient: 2.94; SE: 0.87, p=0.0008) when compared to patients with OSA. Among the clinical determinants of OHS, neither BMI nor AHI showed associations with any postoperative outcomes in univariable or multivariable regression. CONCLUSIONS: Better emphasis is needed on preoperative recognition of hypercapnia among patients with OSA or overlap syndrome undergoing elective NCS<br>Revisión por pares

Obesity and metabolic syndrome are associated with increased risk of advanced prostate cancer, more aggressive high grade disease and increased risk of death from prostate cancer. Androgen targeted therapies can rapidly induce symptoms similar to metabolic syndrome in patients, affecting health and quality of life. The development of therapeutics which could target metabolic dysregulation in addition to cancer growth is urgently needed. This thesis established a new mouse model of metabolic syndrome and assessed components of the ghrelin axis as treatments of prostate cancer. Importantly, an association between the obesity hormone neurotensin, metabolic dysregulation, and androgen-independent prostate cancer was revealed.

Obesity prevalence is higher in Down syndrome (DS) than in the general population. Beyond metabolic alterations, individuals with DS present increased impulsivity, a trait observed in obese people and in compulsive eaters that may affect their control of food intake. In this Thesis, we used a trisomic DS mouse model (Ts65Dn) to understand the behavioral component of obesity in DS and explore some possible underlying mechanisms. Our meal pattern analysis revealed longer and slowly meals in Ts65Dn mice, leading to reduced eating rate, which may be associated to the mandible hypoplasia described in both human and mice. When exposed to obesogenic environments, Ts65Dn mice showed higher preference for energy-dense food, gained more weight in specific conditions and scored higher in compulsivity and inflexibility tests than WT mice, as measured by binge eating during limited access and persistence of consumption of quine adulteration of energy-dense food. High performance liquid chromatography revealed reduced levels of dopamine in prefrontal cortex in Ts65Dn mice. This could lead to higher reward sensitivity that in turn would facilitate overeating as a compensatory response to restore optimal dopamine levels. Feeding behavior is also regulated by hormones and other circulating signals. We detected higher plasma leptin and glucose levels along with reduced insulin levels in Ts65Dn mice. Upon a glucose challenge, Ts65Dn mice showed reduced glucose-stimulated insulin response both in vivo and in vitro, suggesting a deficient insulin secretion or the reduced pancreatic mass. Indeed, we detected that Ts65Dn mice had altered plasma profile for some markers of inflammation and oxidative damage, in agreement with the high prevalence of autoimmune diseases and diabetes in DS people. We also explored the involvement of the serine/threonine kinase DYRK1A, a candidate DS gene, in obesity and feeding behavior. Dyrk1A overexpression was sufficient to recapitulate some behavioral aspects associated to overeating in DS, but with a distinct profile. We conclude that increased obesity prevalence in DS is explained by both metabolic and behavioral alterations, in part driven by a hypodopaminergic status, and that Dyrk1A overexpression is only involved in specific DS obesity phenotypes.<br>La prevalencia de obesidad es más alta en el síndrome de Down (SD) que en la población general. Más allá de las alteraciones metabólicas, los individuos con SD tienen mayor impulsividad, rasgo común en personas obesas y en comedores compulsivos, que pueden afectar el control de la ingesta de alimentos. En esta Tesis, se ha utilizado un modelo de ratón trisómico (Ts65Dn) para comprender el componente de comportamiento en el desarrollo de la obesidad en SD. Nuestro análisis del patrón de ingesta mostró que los ratones Ts65Dn comen más lento que los euploides, lo que podría estar asociado con la hipoplasia mandibular descrita en ratones y humanos con SD. Cuando los ratones Ts65Dn son expuestos a ambientes obesogénicos, comen mayores cantidades de dietas hipercalóricas, engordan más en determinadas condiciones y puntúan más alto en pruebas de compulsividad e inflexibilidad que los ratones euploides. La cuantificación de los niveles de monoaminas mediante cromatografía líquida reveló que los ratones Ts65Dn presentan niveles más bajos de dopamina en corteza prefrontal. Dado que las dietas hipercalóricas promueven la liberación del neurotransmisor en el circuito de recompensa, el sobre consumo de las mismas podría indicar un intento de restaurar los niveles óptimos de dopamina. La regulación de la ingesta también depende de otras señales circulantes. Detectamos que los ratones Ts65Dn tienen mayores niveles de leptina y glucosa en plasma y niveles más bajos de insulina que los euploides. La administración exógena de glucosa produjo una menor respuesta secretoria de insulina en los ratones Ts65Dn in vivo e in vitro. Además, diversos marcadores de inflamación y estrés oxidativo son más elevados en los ratones Ts65Dn, en consonancia con la mayor incidencia de enfermedades autoinmunes y diabetes en personas con SD. En esta Tesis también se ha explorado la contribución de la proteína serina / treonina quinasa DYRK1A, un gen candidato para SD en la obesidad e ingesta. La sobreexpresión de Dyrk1A es suficiente para recapitular algunos comportamientos asociados a la ingesta compulsiva, pero con un perfil distinto al observado en el modelo trisómico. Concluimos que la prevalencia de la obesidad en SD se explica por alteraciones tanto metabólicas como conductuales, en parte como consecuencia de un estado de hipodopaminergia, y que la sobreexpresión de Dyrk1A está implicada en fenotipos específicos de la obesidad en SD.

Tableau d'honneur de la FÉSP<br>L'obésité et son large spectre de maladies associées ont atteint des proportions pandémiques inquiétantes, soulignant la nécessité d’identifier des stratégies alternatives afin de lutter contre ce problème. À ce titre, les régimes riches en fruits et légumes représentent des déterminants bien établis d'une incidence plus faible de ces désordres métabolique. Grandement soutenus par des évidences épidémiologiques reliant les régimes riches en polyphénols et un meilleur état de santé, des efforts considérables ont été déployés afin d’étudier les bienfaits de ces métabolites secondaires des plantes. Malgré tout, les mécanismes par lesquels ces phytoéléments améliorent la santé métabolique demeurent encore mal compris, ce qui en justifie une étude plus approfondie. D’autre part, de plus en plus d’évidences indiquent que les bactéries intestinales exercent un important contrôle sur des aspects clés du métabolisme, et on comprend aujourd’hui que plusieurs phytoéléments de baies ont une biodisponibilité limitée, atteignant ainsi le colon qui abrite la plus vaste part du microbiote intestinal. Le travail présenté dans cette thèse vise donc à étudier l’impact de phytoéléments de baies sur le syndrome métabolique de souris soumises à une diète obèsogène et d’en comprendre le rôle du microbiote intestinal dans ces effets. En traitant quotidiennement ces animaux avec des extraits riches en polyphénols d'une gamme de baies aux compositions polyphénoliques variées, nous avons montré que les extraits les plus bioactifs (c.- à-d., canneberge, cloudberry, alpine bearberry, lingonberry et camu camu) partagent la capacité de diminuer l'inflammation intestinale, l’entotoxémie métabolique, la stéatose hépatique et la résistance à l'insuline. L'analyse des populations microbiennes fécales par séquençage du gène 16S ARNr a révélé que l'état métabolique amélioré lié à l'administration de ces extraits était associé à un remodelage draconien du microbiote intestinal, marqué par une expansion d'Akkermansia muciniphila. Cette bactérie intestinale est fortement associée à un faible niveau d’adiposité chez l’humain et son administration à des souris obèses a été montrée suffisante pour renverser le syndrome métabolique. Par ailleurs, les résultats présentés dans cette thèse suggèrent que les polymères de polyphénols, à savoir les proanthocyanidines et les ellagitannins, pourraient bien être des iv molécules clés dans les effets bénéfiques observés, ouvrant la voie à plus de recherche en ce sens. L’ingestion régulière de ces polyphénols par la consommation de canneberges, de cloudberry, d'alpine bearberry, de lingonberry et de camu camu représentent donc une stratégie efficace pour la prévention de désordres métaboliques associés à l’obésité. Cet ouvrage ouvre ainsi à de nouveaux concepts mécanistiques, ciblant l’axe intestin-foie et le microbiote intestinal pour expliquer les effets bénéfiques des polyphénols sur la santé métabolique.<br>Obesity and its wide spectrum of associated diseases have reached worrisome pandemic proportions, underscoring the need for alternative strategies to fight this problem. Plant-rich diets are well-established determinants of a lower incidence of obesity-related diseases, and fruits are important components of these diets. Supported by strong epidemiological evidence linking polyphenol-rich diets and better health status, research has been focused on the potential health effects of these plant secondary metabolites, albeit the mechanisms by which these poorly bioavailable phytonutrients improve metabolic health remains are not yet fully understood. Since there is compelling evidence for a relationship between host metabolic control and the gut microbiota, the work presented in this thesis aimed to investigate the impact of polyphenol-rich berry extracts on features of the metabolic syndrome in diet-induced obese mice. The work presented in this thesis also focuses on the relationship between putative gut microbial alterations driven by dietary polyphenols and its relevance to host metabolism. By daily treating dietinduced obese mice with polyphenol-rich extracts of a wide range of berries (with varied polyphenolic concentration and composition) we demonstrated that the most bioactive extracts (i.e., cranberry, cloudberry, alpine bearberry, lingonberry and camu camu) shared in common the ability to dampen intestinal inflammation and bacterial lipopolysaccharide leakage to systemic circulation, findings associated with reduced hepatic steatosis and improved insulin resistance. 16S rRNA genebased analysis of fecal DNA revealed that the improved metabolic status linked to the administration of these polyphenolic extracts was associated with a drastic gut microbial remodeling, marked by a consistent bloom of Akkermansia muciniphila. This gut bacterium is strongly associated with leanness in humans and its administration to obese mice reversed features of the metabolic syndrome. The findings presented in this thesis suggest that polymers of polyphenols, namely proanthocyanidins and ellagitannins, may have a superior impact on the gut-liver homeostasis, supporting further research on these particular classes of phenolic phytonutrients. While bringing evidence that substantiate the regular consumption of sources of proanthocyanidins and ellagitannins as a strategy to prevent prevalent chronic diseases associated with obesity, this work provides novel mechanistic insights pointing to the gut-liver axis and the gut microbiota as primary targets of dietary polyphenols in order to improve metabolic health.

This thesis has been prepared in a paper based format and comprises of three stand-alone papers. Paper 1, a systematic review; Paper 2, an empirical study; and Paper 3, a critical appraisal and reflection of the work. Paper 1 has been prepared for submission to Appetite. The paper presents a systematic literature review of studies measuring or reporting potential psychological mechanisms within Night Eating Syndrome (NES). Databases were systematically searched and 20 studies were included in the review. The quality of evidence was mixed and NES was identified and diagnosed in a variety of ways. Studies utilised a variety of different instruments to identify thirteen psychological mechanisms. Syntheses of the studies suggest that there are distinct overlapping features within these mechanisms and five overarching themes were identified to accommodate these overlapping features. Suggestions are made relating to the potential function of the identified psychological mechanisms within NES.Paper 2 has been prepared for submission to Appetite. The paper is a qualitative study exploring the relationship between NES and the experience of emotion specifically from the perspective of patients identified as obese. Ten participants were interviewed and a constructivist grounded theory approach was used to analyse transcripts. A key category to emerge from the analysis was termed 'Emotional Hunger'; reflecting an urge or need to satiate a set of underlying unmet emotional needs. 'Emotional hunger' was underpinned by the following six interrelated themes: (1) The development of a relationship with food; (2) Loss; (3) The significance of night time; (4) A separation of the body and mind; (5) Why I eat, not what I eat; and (6) Consequences of night eating. The clinical implications of the findings are discussed with reference to existing literature. Paper 3 is not intended for publication. The paper provides a critical review of the research process, in which the strengths and weaknesses of the systematic review and empirical study are discussed. Personal and professional reflections on the experience of conducting a systematic review and an empirical study are explored. The clinical implications of the research are also discussed.

Purpose: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including high waist circumference and blood pressure, elevated triglyceride, glucose, and, insulin concentrations and low high density lipoprotein cholesterol concentrations. The prevalence of MetS in overweight and obese adolescents ranges from 10 to 66% depending of the definition used and the population studied. Obese adolescents are more prone to have MetS, highlighting the necessity of designing effective none pharmacological interventions targeting the specific needs of adolescents and to improve the management of the metabolic syndrome. Objectives: The objectives of this thesis were first, to perform a secondary data analysis of the Healthy Eating Aerobic and Resistance Training in Youth (HEARTY) trial to determine the effects of different modalities of exercise training on the prevalence of the MetS and second, to do a critical analysis of the literature surrounding the MetS concept and diagnostic for the pediatric population. Methods: Among the 304 participants of the HEARTY trial, 65 (21%) participants were classified as having MetS by the International Diabetes Federation. Measures of waist circumference, blood pressure, fasting plasma concentrations of lipids, glucose and insulin and prevalence of MetS were compared to baseline and post-6 months intervention (Aerobic training, Resistance training, Combined aerobic and resistance training and Control). Results: There were no significant changes in the prevalence of MetS within and between Aerobic, Resistance, Combined aerobic and resistance and Control groups after the 6-month intervention. However, significant improvements in MetS parameters were observed from baseline to post-intervention within groups. Aerobic and Resistance training alone significantly decreased waist circumference and systolic and diastolic blood pressure. Combined aerobic and resistance significantly decreased triglyceride concentrations and increased high density lipoprotein cholesterol concentrations whereas Control significantly decreased systolic blood pressure and insulin levels. Conclusions: Exercise, regardless of the modality, and diet counseling were not statistically effective for reducing the prevalence of MetS but did improve some of the independent MetS parameters. The absence of statistical difference in the prevalence of the MetS may be due to a lack of statistical power. Moreover, the critical analysis of the MetS literature bring us to conclude that the first step towards a standard definition of MetS for the adolescent population is to define the true clinical purpose of a MetS diagnostic in the pediatric population.

A pig model of childhood obesity was used to study the effects of dietary energy on body adiposity, and blood parameters associated with impaired glucose clearance. Prepubertal female pigs weaned at 21 d of age were fed control (CON), refined sugar (SUG), fat (FAT), and sugar-fat (SUGFAT) diets in a completely randomized arrangement for 16 wk. Calories from fat were 8.9% for CON, 5.6% for SUG, 35.5% for FAT and 32.3% for SUGFAT. Calories from sugar were 36.0% for SUG and 30.7% for SUGFAT. Adding fat, sugar or both to diets increased (P < 0.003) calorie intake. Percentage body fat was higher (P < 0.0001) in all treatments compared to CON, and in SUGFAT and FAT compared to SUG. Ultrasound back fat depth was positively correlated (r2 = 0.909; P < 0.001) with percentage body fat and negatively (r = 0.912; P-value ) with percentage body protein. Area under the curve (AUC) in response to oral glucose tolerance at 14 wk was higher (P < 0.03) in FAT (+14.6%) and SUGFAT (+25.5%) pigs compared to CON. Glucose AUC from sugar-fed pigs was not different (P = 0.2) from fat alone-fed pigs. Adding sugar, fat, or their combination to diets increased (P < 0.008) blood glucose and decreased (P < 0.0009) plasma insulin AUC. These data show that inclusion of fat and refined sugar in pig diets increases body adiposity and impairs glucose homeostasis and suggests that the composition of calories consumed may have different effects than simply consumption of excess of calories.<br>Master of Science

Metabolic Syndrome (MetS) is a collective term for a cluster of disorders, including dysglycemia, central obesity, dyslipidemia, hypertension, and eventual end organ damage. The combination of these disorders increases the risk of many kinds of end organ damages, including coronary heart disease, kidney failure, and cirrhosis. MetS is highly prevalent in the United States, affecting one third of the U.S. population in a 2009 estimate. The Lyon strains are three rat strains selectively inbred from the same colony of outbred rats for different blood pressure levels. The Lyon Hypertensive (LH) strain, in addition to its essential hypertension phenotype, also harbors many disorders found in MetS. The Lyon Normotensive (LN) rat strain is completely devoid of these symptoms, while Lyon Low-pressure (LL) is obese but is resistant to other traits of MetS. Rat chromosome 17 (RNO17) has previously been linked with many of MetS' phenotypes in Lyon Hypertensive (LH). In this project, we are using a mixture of genetical genomics and systems biology methods to identify genetic elements that may cause the LH phenotype. Divergent haplotype blocks between the Lyon strains were first identified by the analysis of the distribution of observed strain differences (OSD) calculated from the result of genome resequencing. Divergent haplotype regions totaling less than 16% of the rat genome that contain more than 95% of the identified SNPs in each of the three pairwise comparisons between the Lyon strains have been identified; in particular, there are 14 divergent haplotype blocks between LH and LN spanning 7.7% of RNO17 that harbor more than 97% of SNPs identified on RNO17. Twenty-five genes in these regions were thus identified as potential genetic determinants for MetS. Phenotypic QTLs (pQTL) and expression QTLs (eQTL) mapping from a cohort of male LH × LN F2 rats were performed by putting the cohort on a 15-week phenotyping protocol and genome-wide genotyping. Total liver RNA from 36 individuals from the cohort were sequenced to provide expression data for eQTL mapping. We have mapped 22 pQTLs that are statistically linked to 15 traits, with RNO17 linked to 15 traits associated with blood pressure, leptin and body weight. We have also identified 1,200 eQTLs from this cohort, including 11 eQTLs with cis-linkage with one or more genes. On RNO17, we have identified two SNPs between 29-39 Mb which are significantly linked to the expression of 85 genes; the only gene with cis-linkage with these SNPs, RGD1562963, was hence identified as a putative master regulator. Transcriptome analyses were then performed on the Lyon parental animals; the total liver and kidney of RNA from 6 each of LH, LL and LN strains that were subjected to the same 15-week phenotyping protocol were sequenced for differential expression analysis, gene coexpression network analysis and quantitative trait transcript analysis. Differential expression analysis identified 4 genes on RNO17's divergent haplotype regions: Cul2 and the aforementioned RGD1562963 for liver, Amph and Bambi for kidney. Quantitative trait transcript analyses have shown significant correlations between the expressions of these four genes with one or more of the traits of the animals treated, validating their status as potential genetic determinants for MetS. However, out of the 84 genes that RGD1562963 potentially regulates, only two other genes (Cul2 and Supt4h1) have significant correlations with one or more traits. Gene coexpression network analyses have shown a relationship between genes on the TGF-β pathway and the differentially expressed genes in the kidney, supporting our speculation on the hyperactivity of the TGF-β system in the etiology of the LH phenotypes. An LH-17LN consomic strain was also generated by introgressing an LN copy of RNO17 onto the LH genomic background to validate in vivo the role of RNO17 in the etiology of MetS symptoms in LH. We have observed that the consomic strain has significantly decreased body weight, adiposity, blood pressure, and inter-week blood pressure differences that may be a surrogate for salt sensitivity. Thus, the role of RNO17 on the LH genotype is validated. In summary, we have been able to identify, by in vivo and in silico methods, that RNO17 is related to the MetS traits in LH; that 4 genes, Amph, Bambi, Cul2, and RGD1562963, are potential genetic contributors to RNO17's effects; and that their effects may include, but are not limited to, the activation of TGF-Β signals.

The overall aim was to contribute to the development of effective self-management lifestyle education for management of cardiovascular and diabetes risk in people with metabolic syndrome (MetS). An additional aim was to elicit views on the use of waist circumference measurement to assess health risk due to overweight and obesity, and identify strategies to promote waist measurement. A qualitative study was conducted to determine the knowledge and attitudes of patients and primary care health practitioners concerning waist size measurement. A systematic review (and meta-analysis) was conducted to review the existing evidence on effectiveness of interventions for reducing diabetes and cardiovascular risk in people with MetS. An evidence based group lifestyle education programme was developed and tested in a randomised controlled trial: The Reversal Intervention for Metabolic Syndrome (TRIMS) study. Key findings: -Healthcare professionals were generally aware of a link between a large waist size and health risks; practical barriers to using waist measurement included lack of time, extra workload and financial implications. For patients, being given an explanation of the assessment appeared to be what was most important to them. -The benefits of both lifestyle and pharmacological interventions to reverse MetS were indicated, by the meta-analysis, with lifestyle being the most effective. -The TRIMS education programme was well received; people felt positive about making lifestyle changes and improving their future health. -After 6-months follow-up the TRIMS programme was effective at reducing waist size, hip circumference, weight, and body mass index, and increasing unsaturated fat intake; reversal of MetS was not significantly different between the intervention and control groups. Based on the findings from this programme of work, recommendations are provided for future research and clinical practice in order to promote better management of cardiovascular and diabetes risk in people with MetS.

5a-Reductase 1 (5aR1) metabolises steroids such as glucocorticoids and androgens and is highly expressed in the livers of mice. Genetic disruption of 5aR1 leads to adverse metabolic consequences in mice and pharmacological inhibition in humans induces peripheral insulin resistance. I hypothesised that these effects are due to increased hepatic glucocorticoid action and firstly set up an experimental paradigm using A-348441, a liver-selective glucocorticoid receptor antagonist, to assess the contribution of hepatic glucocorticoid action. A-348441 was then utilised to assess whether changes in hepatic glucocorticoid signalling underpinned metabolic changes in: 1) a genetic model where the gene for 5aR1 has been disrupted, and 2) a pharmacological model using dutasteride, a dual 5aR1, R2 inhibitor. Previous work with A-348441 has demonstrated it can lower blood glucose levels in ob/ob mice. However, monogenic models of obesity are not fully representative of idiopathic obesity, which is commonly related to diet. Therefore, I utilised a mouse model of high fat dietary challenge to determine the effects of A-348441 in a more relevant model. High fat diet worsened metabolic indices such as body weight and weight gain, adipose tissue depot mass, fasting insulin and insulin response to a glucose challenge. A-348441 improved metabolic health of mice on high fat diet, preventing high fat-induced body weight gain, total white adipose depot weight gain and attenuating high fat-induced elevations in fasting plasma insulin, fasting glucose and insulin response to a glucose tolerance test. Importantly, hepatic glucocorticoid receptor antagonism did not change plasma corticosterone concentrations, indicating that glucocorticoid receptor antagonism was limited to the liver and thus demonstrating that hepatic glucocorticoid action plays a major role in high fat dietinduced metabolic phenotype. Using A-348441, I then went on to test the contribution of hepatic glucocorticoid action to the adverse metabolic phenotype in wild-type and 5aR1 knockout mice also under a high fat dietary challenge; two timescales were explored – 10 weeks with A- 348441 administered from the start and 6 months with A-348441 introduced after 5 months of high fat diet. 5aR1 knockout mice were overall more insulin resistant and had fattier livers than the wild-type mice at 10 weeks regardless of diet consumed. High fat diet overall worsened metabolic indices - increasing body weight, weight gain, adipose tissue depot mass, fasting insulin and insulin response to a glucose challenge in both genotypes and at both time points. Hepatic glucocorticoid receptor antagonism in 5aR1 knockout mice prevented high fat diet-induced metabolic consequences as expected in the 10-week high fat diet model, but not in the 6-month experiment; hyperinsulinaemia and weight gain were attenuated in the 10-week high fat diet model but not the 6-month high fat diet model, suggesting hepatic glucocorticoid receptor antagonism can prevent, but not reverse, high fat diet-induced metabolic consequences. However, A-348441 did not have a bigger effect on ameliorating the worsened metabolic state of the 5αR1 knockout mice. This suggests that increased hepatic glucocorticoid action does not underpin the adverse phenotype reported in the 5aR1 knockout mice. Dutasteride is a dual 5aR inhibitor prescribed to men for benign prostate hyperplasia or prostate cancer. I then recapitulated the human experiment where 5aR was pharmacologically inhibited and investigated the effects of dutasteride in mice. Inhibition of 5aRs in mice impaired insulin sensitivity, with increased insulin response to glucose tolerance test and also increased liver triglyceride levels; body weight, total adipose depot weight, fasting insulin, fasting glucose or glucose response to a glucose tolerance test were not changed by dutasteride. A-348441 reduced this hyperinsulinaemia but, as in other models, did not reduce the increased liver triglyceride levels. This suggests hepatic glucocorticoid action plays a substantial role in the development of insulin resistance caused by 5aR inhibition, but not in the development of hepatic steatosis. Therefore, adverse metabolic changes as a result of 5aR1 inhibition with dutasteride may be driven by altered hepatic glucocorticoid metabolism. Furthermore, metabolic changes caused by lifelong 5aR1 disruption are not responsive to short-term hepatic glucocorticoid receptor antagonism and altered androgen signalling may play a greater role. In conclusion, targeting the hepatic glucocorticoid receptor may be beneficial in restoring metabolic homeostasis in diet-induced obesity.

Les patients atteints de lupus érythémateux systémique ont une augmentation de la prévalence du syndrome métabolique (MetS) mais les mécanismes sous-jacents ne sont pas connus. Le récepteur de type Toll 7 (TLR7), qui reconnait de l’ARN simple brin, joue un rôle important dans la défense anti-microbienne de l’hôte, mais contribue également au développement et à la progression du lupus. Cependant, l’implication de TLR7 dans le MetS est inconnue. L’objectif de mon projet de thèse était d’explorer l’idée nouvelle que la signalisation de TLR7 peut conduire non seulement au lupus mais aussi à des anomalies métaboliques.Nous avons trouvé que l’obésité induite par un régime riche en gras (régime HFD) a conduit à une exacerbation du lupus et de paramètres métaboliques dans des souris TLR8ko, qui développent spontanément une auto-immunité de type lupique à cause d’une augmentation de la signalisation de TLR7 dans les cellules dendritiques (DCs). Au contraire, sous un régime HFD, les souris TLR7/8ko n’ont pas développé de lupus, et les souris TLR7ko et TLR7/8ko ont été protégées contre les anomalies métaboliques incluant l'augmentation de poids et l’intolérance au glucose. De manière intéressante, dans des souris sauvages (WT) le régime HFD a conduit à une augmentation de l’expression de TLR7 et de la production de TNF par les DCs spléniques et hépatiques, et ce phénotype était plus profond dans les souris TLR8ko. Mon étude montre l’implication de la signalisation de TLR7 dans l’interconnexion entre le lupus et les anomalies métaboliques, donc cibler TLR7 pourrait constituer une nouvelle approche comme thérapie contre le lupus et les maladies métaboliques<br>Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defence, but also contributes in the initiation and progression of SLE. However, the implication of TLR7 in MetS is unknown. The objective of my PhD project was to explore the novel idea that TLR7 signalling can lead not only to SLE but also to metabolic abnormalities. We found that high fat diet (HFD)-induced obesity led to exacerbation of lupus and metabolic parameters in TLR8ko mice, which develop spontaneous lupus-like disease due to increased TLR7 signalling by dendritic cells (DCs). In contrast, upon HFD TLR7/8ko mice did not develop SLE, and both TLR7ko and TLR7/8ko mice were protected from metabolic abnormalities including body weight gain and glucose intolerance. Interestingly, in wild-type mice HFD led to an increase of TLR7 expression and TNF production by hepatic and splenic DCs, and this phenotype was more profound in TLR8ko mice. My study uncovers the implication of TLR7 signalling in the interconnection of SLE and metabolic abnormalities, thus targeting TLR7 might be a novel approach as a tailored therapy in SLE and metabolic diseases

Thesis (M.S.)--Southern Illinois University Carbondale, 2008.<br>"Department of Physiology." Keywords: Maternal, Metabolic, Obesity, Sweeteners. Includes bibliographical references (p. 103-111). Also available online.

Background Physical inactivity causes obesity, a condition which is related to insulin resistance, hypertension, diabetes mellitus, dyslipidemia and the metabolic syndrome (MS). MS is the collective description of lifestyle diseases associated with significant morbidity and premature mortality. MS has recently been observed in youth, and if left untreated could lead to cardiovascular diseases. Regular physical activity (PA) and exercise training appear to modify the independent risk factors for MS and cardiovascular diseases, and has a positive effect on waist circumference, blood pressure, body fat percentage, insulin sensitivity and arterial compliance. Aims The aim of this study was to determine the relationship between body composition and selective markers of the MS, and the extent to which a PA intervention programme will influence selective markers of the MS, body composition and markers of vascular function in black adolescents. Methods Grade 9 classes from two high schools, in a low socio-economic status area near Potchefstroom, participated as the experimental and control group respectively. The experimental group consisted of 194 participants and the control group of 57 participants. The experimental group participated in a 10-week P A intervention. Body mass index, stature, body mass, waist-hip ratio, waist circumference, hip circumference, body fat percentage, fasting serum insulin, fasting plasma glucose, plasma leptin, homeostasis model assessment of insulin resistance (HOMA-IR), systolic blood pressure (SBP), diastolic blood pressure (DBP), Windkessel arterial compliance (Cw), total peripheral resistance, Tannerstage and habitual physical activity were measured. The data were analysed by means of descriptive statistics, Mann-Whitney U-tests, analysis of covariance (ANCOVA), Pearson's correlation analyses and multiple regression models. HOMA-IR and leptin were log transformed before analyses because of the skewed distribution. The Statistica for Windows and SAS computer programmes were used to analyse the data according to the above-mentioned aims of the study. Results and conclusions Firstly, a significant positive association was found between body fat percentage and both SBP (p=O.02) and HOMA-IR (p=O.02) respectively. Girls with a high body fat percentage had higher SBP (p=O.004), DBP (p=O.03), plasma insulin (p=O.004) and HOMA-IR (p=O.004) than girls with normal body fat percentage. Secondly, a 10-week PA intervention led to a significant decrease in SBP (p=O.000061), a trend of decreasing HOMA-IR, and a trend of increasing Cw in black adolescents. Lastly, no significant differences were found in body composition and vascular function variables for the normal-and over-fat group in this study after the 10-week PA intervention. In conclusion, the results of this study showed firstly, that there was a positive association between body fat percentage and SBP and HOMA-IR respectively; and secondly, that PA had a positive effect on some MS markers, namely: SBP and HOMA-IR. Further research regarding PA intervention's influence on the MS in black adolescents should be conducted, as there is clearly a shortage of literature that focuses on this research theme within this South African ethnic group.<br>Thesis (Ph.D. (Human Movement Science))--North-West University, Potchefstroom Campus, 2010.

The objective of this study was to determine the effects of a structured weight loss program that included hypocaloric diet, exercise and dietary supplementation, on weight loss, metabolic syndrome risk factors and antioxidant levels in healthy overweight and obese females. Thirty-seven healthy overweight and obese women (BMI 29.5 ± 2.3 kg/m2, 41.1 ± 7.1 yrs) participated in this study. The subjects were randomized into one of two groups: an exercise, hypocaloric diet and antioxidant supplement (LifePak®; LSANT group, n=20) or an exercise, hypocaloric diet and appetite suppression supplement (HTP Complex® and TēGreen®; LSAS group, n=17). A significant weight loss occurred in both groups after 12 weeks (LSANT: -2.8 ± 2.8 kg and LSAS: -4.3 ± 2.7 kg, p<0.001). Body fat mass, percent body fat, and waist circumference significantly improved in both groups (p<0.05). No significant difference was found between the groups for weight loss (p>0.05). However, a significant difference was found between the groups for body fat mass (LSANT: -1.8 ± 2.6 kg; LSAS: -3.4 ± 2.4 kg, p ≤ 0.05). Glucose, insulin and insulin resistance (HOMA-IR) were significantly decreased in the LSAS group (glucose: -5.0 ± 6.8 mg/dl, p=0.008; insulin: -2.6 ± 3.8 uIU/dl, p=0.013; and HOMA-IR: -0.7 ± 1.0, p=0.012) but not in the LSANT group (p>0.05). There were no significant differences (p>0.05) observed within or between the groups for cholesterol, triglycerides or LDL-c. HDL-c decreased significantly in the LSANT group (-2.9 ± 5.3 mg/dl, p=0.024) but not in the LSAS group (p>0.05). Skin carotenoid scores (SCS) increased significantly within the LSANT group (LSANT: 10950 ± 8395 SCS, p<0.001) but not the LSAS group (p>0.05). Lifestyle intervention that involves a structured hypocaloric diet and increased physical activity results in weight loss and improvements in body composition. However, supplementation with an appetite suppressant (HTP Complex®) did not enhance weight loss beyond what was achieved with a structured lifestyle intervention. Antioxidant supplementation may be of benefit during a weight loss program that incorporates physical activity and a low energy diet.<br>Ph.D.<br>Department of Child, Family and Community Sciences<br>Education<br>Education PhD

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.

Mit dem Beginn der Industrialisierung stieg in den westlichen Kulturen rasant die Prävalenz von Krankheitsbildern wie Adipositas, arterieller Hypertonie, Typ-2-Diabetes Mellitus und Hyperlipidämie, die als Cluster eines multifaktoriellen Krankheitsbildes namens „Metabolisches Syndrom“ (MTS) verstanden werden. Tierstudien, in denen durch die Inhibition der Fettsäuresynthase (FASN) ein rapider Abfall des Körpergewichts in Mäusen erzeilt wurden, bestätigen zunehmend genetische Prädispositionen als ursächlich für die Ausbildung des MTS. Um herauszufinden ob und in welchem Ausmaß das FASN-Gen mit humanen Merkmalen des MTS assoziiert ist, wurde das Gen in 48 nicht verwandten ostdeutschen Probanden sequenziert. Acht repräsentative tagging-SNPs wurden dabei identifiziert, anschließend in 1311 deutschen Probanden (Erwachsene) genotypisiert und in Fall-Kontroll-Studien zwischen 389 schlanken Probanden (BMI ≤ 25kg/m²) vs. 446 adipösen Teilnehmern (BMI ≥ 30kg/m²) sowie zwischen 502 glukosetoleranten Probanden (NGT) vs. 640 Probanden mit Typ-2-Diabetes (T2D) miteinader verglichen. Für den Polymorphismus rs2229422 (P = 1.3x10-5 adjustiert auf Alter, Geschlecht und Diabetes-status) konnten die stärksten Assoziationen mit BMI und weiteren Merkmalen der Fettleibigkeit identifiziert werden (adjustiert P < 0.05). Des Weiteren wurde der zuvor in der Literatur beschriebene protektive Einfluss der Val1483Ile Substitution (rs2228305) gegenüber Adipositas, sowie der geschlechts-spezifische Effekt auf den BMI bestätigt (adjustiert, P = 0.03).

L'obesitat es defineix com una acumulació anormal de greix que pot ser perjudicial per a la salut. Sovint apareix de forma conjunta amb altres factors de risc metabòlic relacionats amb la síndrome metabòlica, com són la dislipidèmia, la resistència a la insulina o el fetge gras no alcohòlic. S'han identificat i investigat diferents compostos bioactius degut a la seva capacitat per a prevenir l'obesitat i les seves malalties relacionades. Entre ells, l'àcid linoleic conjugat (CLA) és un dels compostos més investigats per al control del pes corporal, tot i que s'han notificat diferents efectes adversos associats al seu consum. No obstant això, l'ús d'una sola família de compostos bioactius podria no ser suficient per a corregir de manera eficaç malalties multisistèmiques i altament regulades com l'obesitat i la síndrome metabòlica. Per això, l'objectiu de la present Tesi ha estat avaluar si la co-administració simultània de diferents compostos bioactius (inclòs el CLA, una barreja de proantocianidines de llavor de raïm i antocianines de baies, i l'hidrolitzat proteic de pota de pollastre Hpp11) redueix l'obesitat i/o factors de risc cardiometabòlics associats a l’obesitat d'una manera més eficaç que la seva administració individual. Els nostres resultats van demostrar que l'administració dels isòmers de CLA c9,t11 i t10,c12 a la mateixa proporció i en dosis baixes provoca una disminució del guany de pes corporal induït per una dieta de cafeteria, i, alhora, millora altres factors de risc cardiometabòlics sense presentar cap efecte advers notori relacionat amb el propi consum de CLA. A més, es va observar que la reducció del pes corporal produïda pel CLA és més gran quan el CLA s’administra conjuntament amb l'hidrolitzat de pota de pollastre Hpp11 i la barreja de proantocianidines i antocianidines. Aquest efecte, que podria estar mediat per una millora de la sensibilitat a la leptina a nivell hipotalàmic, tampoc es va acompanyar de cap efecte advers associat a la pròpia pèrdua de pes. Tot just al contrari, la co-administració dels diferents compostos va produir una millora notable en el metabolisme de la glucosa i dels lípids i va mostrar un efecte antihipertensiu molt marcat. Per tant, el nostre ingredient funcional podria ser un molt bon candidat per a ser utilitzat per al control de la síndrome metabòlica.<br>La obesidad se define como una acumulación anormal y perjudicial de grasa. Con frecuencia aparece junto con otros factores de riesgo metabólico relacionados con el síndrome metabólico, como son la dislipidemia, la resistencia a la insulina o el hígado graso no alcohólico. Se han estudiado compuestos bioactivos debido a su capacidad para prevenir la obesidad y enfermedades relacionadas. Entre ellos, el ácido linoleico conjugado (CLA) es uno de los compuestos más investigados para el control del peso corporal, aunque se han notificado diferentes efectos adversos asociados a su consumo. Sin embargo, el uso de una sola familia de compuestos bioactivos podría no ser suficiente para corregir de forma eficaz enfermedades multisistémicas y altamente reguladas como la obesidad y el síndrome metabólico. Por ello, el objetivo de la presente Tesis ha sido evaluar si la co-administración de diferentes compuestos bioactivos (incluido el CLA, una mezcla de proantocianidinas de pepita de uva y antocianinas de bayas, y el hidrolizado proteico de patas de pollo Hpp11) reduce la obesidad y/o sus factores de riesgo cardiometabólicos asociados mas eficazmente que su administración individual. Nuestros resultados demostraron que la administración de los isómeros de CLA c9,t11 y t10,c12 en la misma proporción y en dosis bajas provoca una disminución de la ganancia de peso corporal inducido por una dieta de cafetería, y, a la vez, mejora otros factores de riesgo cardiometabólico sin presentar ningún efecto adverso relacionado con el propio consumo de CLA. Además, se observó que la reducción del peso corporal con el CLA fue mayor cuando el CLA se administró conjuntamente con el hidrolizado de pata de pollo Hpp11 y la mezcla de proantocianidinas y antocianidinas. Este efecto sobre el peso corporal, que podría estar mediado por una mejora de la sensibilidad a la leptina a nivel hipotalámico, no se acompañó de ningún efecto adverso asociado a la propia pérdida de peso. La co-administración de los compuestos produjo una mejora notable en el metabolismo de la glucosa y de los lípidos y un efecto antihipertensivo muy marcado. Por lo tanto, nuestro ingrediente funcional podría ser un muy buen candidato para ser utilizado como nutracéutico o para ser incluido en alimentos funcionales para la prevención y control del síndrome metabólico.<br>Obesity is defined as an excess of fat accumulation that represents a risk to health. It frequently occurs concurrently with other metabolic risk factors related to metabolic syndrome (MetS), such as dyslipidaemia, insulin resistance or non-alcoholic fatty liver disease (NAFLD). Many food bioactive compounds have been identified and further investigated for their ability to prevent obesity and its metabolic associated pathologies. Among them, conjugated linoleic acid (CLA) is one of the dietary bioactive compounds most investigated for weight management, although controversial metabolic results have been reported. However, the use of a single family of bioactive compounds could not be sufficient to correct multisystemic and highly regulated situations such as obesity and its associated metabolic pathologies. Thus, the aim of this Thesis was to evaluate whether the simultaneous co-administration of different bioactive compounds, including CLA, a mixture of grape-seed proanthocyanidins and berry anthocyanins, and the protein hydrolysate from chicken feet Hpp11, could reduce obesity and its associated cardiometabolic risk factors in a much more effective way than its individual administration. Our results demonstrated that the administration of an equal ratio of the CLA isomers c9,t11 and t10,c12 at low doses caused a decrease in the body weight gain induced by a cafeteria diet, and improved other cardiometabolic risk factors, without presenting any CLA-related adverse effects. In addition, the body weight lowering effect of CLA was higher when it was co-administrated with the chicken feet hydrolysate Hpp11 and a mixture of proanthocyanidins and anthocyanidins. This anti-obesity effect, which could be mediated by an improvement of hypothalamic leptin sensitivity, was also not accompanied by any adverse effect of weight loss. On the contrary, MIX produced an improvement on glucose and lipid metabolism and exhibited antihypertensive properties. Thus, MIX could be a good candidate to be used as nutraceutical or to be included in functional foods for the management of metabolic syndrome.

C-reactive protein (CRP), a powerful marker of inflammation and potential mediator in cardiovascular diseases, has been frequently associated with obesity. The extent to which this association varies across sex, ethnicity and age in the general population and in a population with premature coronary disease has not been investigated.To review this association in the general population, we conducted meta-regressions and subgroup analyses in 51 cross-sectional studies. BMI was strongly associated with log(CRP) in adults (Pearson coefficient [r]: 0.36; 95% confidence interval [CI]: 0.30 to 0.42) and children (r: 0.37; 95% CI: 0.31 to 0.43). The association between BMI and log(CRP) was greater in women than men, and greater in North Americans/Europeans than Asians. This association was comparable between boys and girls among North Americans/Europeans with available data. Similar results were obtained when waist circumference (WC) or waist-hip ratio (WHR) was used in the analyses instead of BMI.We then conducted cross-sectional analyses of 728 patients in the GENESIS-PRAXY (GENdEr and Sex DetermInantS of cardiovascular disease: from bench to beyond PRemature Acute Coronary SYndrome) cohort to examine the association between obesity and CRP in a young population (≤ 55 years) with acute coronary syndrome (ACS). Obesity was highly prevalent in this group of patients (40%). Multivariate linear regression showed each of BMI, WC, and WHR to be independently associated with log(CRP), however the addition of a sex interaction term did not reveal a sex difference in the magnitude of effect. Aside from obesity, we found smoking, female sex, and gender identity scores to predict log(CRP). Obesity is associated with elevated levels of CRP in the general population and in young patients with ACS. This association varies according to sex, ethnicity, and age in the general population, but further research is required to clearly understand the extent to which this association varies in patients with premature coronary disease.<br>La protéine C-réactive (PCR), un puissant marqueur de l'inflammation, a été fréquemment liée à l'obésité et proposée comme médiateur potentiel dans les maladies cardiovasculaires. La mesure dans laquelle cette association varie selon le sexe, l'ethnicité et l'âge dans la population générale et dans une population ayant la maladie coronarienne prématurée n'a pas été étudiée.Pour examiner cette association dans la population générale, nous avons effectué des méta-régressions et analyses en sous-groupes dans 51 études transversales pertinentes. L'IMC était fortement associé au log(PCR) chez les adultes (coefficient de Pearson [r] : 0,36; IC 95% : 0,30 à 0,40) et les enfants (r : 0,37; IC 95% : 0,31 à 0,43). L'association entre l'IMC et le log(PCR) était plus élevée chez les femmes que chez les hommes, et plus élevée chez les Nord-Américains/Européens que chez les Asiatiques. Cette association était comparable entre les garçons et les filles Nord-Américains/Européens ayant des données disponibles. Des résultats similaires ont été obtenus lorsque la tour de taille (TT) et le rapport taille-hanche (RTH) ont été utilisés dans les analyses au lieu de l'IMC.Nous avons ensuite effectué des analyses transversales de 728 patients de la cohorte GENESIS-PRAXY (GENdEr and Sex DetermInantS of cardiovascular disease: from bench to beyond PRemature Acute Coronary SYndrome) afin d'examiner l'association entre l'obésité et la PCR dans une population jeune (≤ 55 ans) ayant le syndrome coronarien aigu (SCA). L'obésité est très répandue dans ce groupe de patients (40%). La régression linéaire multivariée démontra que l'IMC, la TT, et le RTH étaient chacun associés indépendamment au log(PCR), toutefois l'ajout d'un terme d'interaction de sexe n'a pas révélé de différences entre les sexes dans l'ampleur de l'effet. Mis à part l'obésité, nous avons trouvé que fumer, le sexe féminin, et l'identité de genre prédisaient le log(PCR).L'obésité est associée avec des taux élevés de PCR dans la population générale et chez les patients ayant le SCA. Cette association varie selon le sexe, l'ethnicité et l'âge dans la population générale, mais des recherches supplémentaires sont nécessaires pour mieux comprendre la mesure dans laquelle cette association varie chez les patients ayant la maladie coronarienne prématurée.

This thesis investigated the role of ghrelin in children with Prader-Willi Syndrome (PWS) - a complex genetic neurodevelopmental disorder which often results in obesity. The data presented in this project provide evidence of new mechanisms of ghrelin regulation in PWS and will form a basis for future work that has potential therapeutic benefit in the areas of hyperphagia (excessive appetite) and obesity in children with PWS.