Rates of obesity (OB) are escalating among Canadian children and youth and the obesogenic environment is likely to cause further increases. An important aspect in providing clinical care to OB children is to have accurate assessment measures, particularly of their body composition and cardiorespiratory fitness. This project entails three interrelated projects aiming to develop novel cardiorespiratory fitness and body composition measurement techniques for an OB pediatric population. The purpose of the first project was to validate a new submaximal fitness protocol specifically geared towards OB children and youth. The second objective of this thesis involved assessing cardiorespiratory efficiency utilizing the Oxygen Uptake efficiency slope. The purpose of the third project was to determine the validity of a half-body scan methodology for measuring body composition in obese children and youth. The goal of developing these novel measurement techniques is improved design and evaluation of interventions aimed at managing pediatric obesity.

L’épidémie de surpoids et d’obésité concerne également les jeunes enfants, se caractérise par d’importantes inégalités sociales et entraîne des conséquences graves pour la santé à court, moyen et long terme. Les comportements impliqués dans la balance énergétique, à savoir l’activité physique, l’exposition à la télévision et l’alimentation pourraient jouer un rôle déterminant vis-à-vis du risque d’obésité du jeune enfant et sont potentiellement modifiables. Les objectifs de ce travail étaient d’étudier l’association entre ces comportements, considérés isolément mais aussi de manière intégrée sous forme de clusters multi-comportementaux à 2 et 5 ans, et le risque d’obésité et ce, séparément chez les filles et les garçons. Le risque d’obésité a été appréhendé au travers de la masse grasse à 5 ans et de l’âge au rebond d’adiposité. Le travail s’appuie sur les données de la cohorte EDEN. A 2 ans, le temps de jeux extérieurs chez les filles et le temps passé devant la télévision chez les garçons étaient respectivement associés inversement et positivement au pourcentage de masse grasse à 5 ans. A 2 ans, nous avons identifié des clusters multi-comportementaux caractérisés principalement par la fréquence de consommation d’aliments et de boissons à forte densité énergétique. Ces derniers n’étaient pas liés longitudinalement au pourcentage de masse grasse à 5 ans. Les clusters identifiés à 5 ans (4 clusters chez les filles et 2 chez les garçons) étaient principalement différentiés par l’exposition à la télévision ; chez les garçons la surexposition à la télévision était en outre associée à de moins bonnes habitudes alimentaires, tandis que chez les filles toutes les combinaisons possibles de niveaux d’exposition à la télévision et d’activité physique en extérieur (jeux/marche) étaient observées au sein des clusters. Les filles appartenant au cluster « Exposition très élevée à la télévision – Activité physique extérieure élevée » à 5 ans avaient un pourcentage de masse grasse plus élevé que celles du cluster de référence « Exposition modérée à la télévision – Activité physique extérieure plutôt élevée ». Par ailleurs, une plus forte adhésion au profil alimentaire «Aliments transformés, ou type fast-food » (identifié dans des travaux précédents) à 2 ans était associée à un âge plus précoce du rebond d’adiposité, défini comme intervenant en moyenne avant 3,7 ans dans les 2 sexes. Enfin, la position socioéconomique était inversement associée au temps passé devant la télévision ainsi qu’aux clusters caractérisés par une surexposition à la télévision et/ou de moins bonnes habitudes alimentaires ou de repas. Ces travaux montrent que tous les comportements impliqués dans la balance énergétique influencent le risque ultérieur de surpoids et d’obésité, mais avec une temporalité différente, sur des marqueurs de risque distincts et de façon variable en fonction du sexe de l’enfant et de son origine sociale. Ils montrent aussi que ces comportements se combinent de façon complexe et variable selon le sexe, et suggèrent que certaines typologies comportementales confèrent un risque plus élevé d’accumulation excessive de masse grasse. Ces résultats nous invitent à mettre en place des stratégies de prévention de l’obésité intégrant tous les comportements impliqués dans la balance énergétique et ce dès le plus jeune âge. Les efforts doivent viser à réduire le temps passé devant la télévision, en particulier dans les familles les plus modestes, tout en promouvant l’activité physique, en particulier en encourageant les petites filles aux jeux actifs à l’extérieur. En parallèle, il semble pertinent d’inciter les familles, et ce dès la grossesse, à adopter une alimentation proche des recommandations, en insistant sur l’importance des habitudes de repas, télévision éteinte et sans mise à disposition de boissons sucrées. Compte tenu de son approche holistique de la famille, le médecin généraliste est un vecteur idéal de ces messages de prévention. / The epidemy of obesity concerns also young children, is characterized by important social inequalities and has important consequences on health in the short, medium and long-term. Energy balance-related behaviors, namely physical activity, television exposure and diet, may be important in young children in determining subsequent obesity risk, and are potentially modifiable. The objective of this work was to examine the association between energy balance-related behaviors, considered in isolation or in combination (via cluster analysis) at 2 and 5 years of age, and obesity risk in boys and girls separately. Obesity risk was assessed by the percentage of body fat at 5 years and the age of the adiposity rebound. The work is based on data from the EDEN birth cohort. At 2 years, outdoor play time and television watching time were respectively, inversely and positively associated with the percentage of body fat at 5 years. At 2 years, 2 clusters emerged that were essentially characterized by opposite eating habits, with intake of energy-dense food and sweetened beverages being the most discriminating feature. At 5 years, clusters (2 in boys, 4 in girls) were mainly differentiated by the level of television exposure; in boys, high television exposure combined with unhealthy eating habits, while in girls, all possible combinations of the level of television exposure and time spent in outdoor physical activity (play and walk) were observed within clusters. Girls belonging to the ‘Very high television exposure – High outdoor physical activity’ cluster had a significantly higher percentage of body fat than girls in the reference cluster (labeled ‘Moderate television exposure – rather high outdoor physical activity’). Furthermore, a higher score on the ‘Processed and fast foods’ pattern (identified in a previous Eden analysis) at 2 years was associated with an earlier age of adiposity rebound (here defined as before 3.7 years on the average in both sexes). Maternal education level (taken as a general indicator of socio-economic position (SEP)) was inversely related to television viewing time as well as clusters characterized by a high level of television and/or less favorable eating habits (eating while the television is on and drinking sweetened beverages at mealtimes). These results suggest that all three-energy balance-related behaviors influence the subsequent risk of obesity, but with different timing of influence, on distinct markers of obesity risk, and in a way that differ according to the child’s sex and his/her family’s SEP. Furthermore, results suggest that these behaviors combine in complex ways that differ in boys and girls, and that identification of behavioral typologies based on specific combinations of behaviors may be useful to distinguish groups of children with different levels of risk. These results plead for integrated obesity preventive strategies targeting all three-energy balance-related behaviors, and implemented as early as possible, ideally before the age of 2. Efforts should strive to decrease television viewing time, especially in low SEP families, while simultaneously promoting physical activity, in particular by encouraging young girls to engage in active outdoor play. In parallel, it appears important to encourage mothers, especially from low SEP families, to follow diet guidelines and adopt favorable mealtime routines (e.g., turning off the television during meals, and proposing water rather than sodas at mealtime). Because of their frequent and continued contact with parents and their children throughout childhood, family physicians are particularly well positioned to help parents promote and support the development of early healthful physical activity and diet habits of children, starting in early childhood.

Di-(2-ethylhexyl)-phthalate (DEHP), an ubiquitous environmental contaminant, has been shown to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies, but the underlying mechanisms are still unknown. We therefore tested the hypothesis that chronic DEHP exposure causes impaired insulin sensitivity, affects body weight, adipose tissue (AT) function and circulating metabolic parameters of obesity resistant 129S6 mice in vivo. An obesity-resistant mouse model was chosen to reduce a potential obesity bias of DEHP effects on metabolic parameters and AT function. The metabolic effects of 10-weeks exposure to DEHP were tested by insulin tolerance tests and quantitative assessment of 183 metabolites in mice. Furthermore, 3T3-L1 cells were cultured with DEHP for two days, differentiated into mature adipocytes in which the effects on insulin stimulated glucose and palmitate uptake, lipid content as well as on mRNA/protein expression of key adipocyte genes were investigated.We observed in female mice that DEHP treatment causes enhanced weight gain, fat mass, impaired insulin tolerance, changes in circulating adiponectin and adipose tissue Pparg, adiponectin and estrogen expression. Serum metabolomics indicated a general increase in phospholipid and carnitine concentrations. In vitro, DEHP treatment increases the proliferation rate and alters glucose uptake in adipocytes. Taken together, DEHP has significant effects on adipose tissue (AT) function and alters specific serum metabolites. Although, DEHP treatment led to significantly impaired insulin tolerance, it did not affect glucose tolerance, HOMA-IR, fasting glucose, insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does not cause impaired glucose metabolism at the whole body level.

Dietary intervention remains a popular, albeit challenging, approach for combating obesity. In recent years, dietary interventions that increase consumption of medium-chain triglycerides (MCT) instead of long-chain triglycerides (LCT) have gained attention. Pre-clinical research has demonstrated that rats fed a high-fat diet (HFD) induce adiposity, but a dietary shift from LCT to MCT suppresses this effect. To date, the extent to which this effect operates via suppressed hyperphagia is not fully understood. In the present study, we sought to determine how consuming a HFD composed of different fat types affects energy intake, adiposity, and hippocampal brain-derived neurotropic factor (BDNF) levels. Rats were assigned to one of four diet groups – rat chow (CHOW), LCT-enriched HFD (LCT-HFD), MCT-enriched HFD (MCT-HFD), or coconut oil-enriched HFD (COCO-HFD), which composes a mixture of LCT and MCT. In Experiment 1, all animals were given <i>ad libitum</i> access to their assigned diet, whereas in Experiments 2 and 3, HFD-subjects were pair-fed to CHOW to prohibit hyperphagia. In Experiments 1 and 2, subjects were aged 20-24 weeks, whereas in Experiment 3, subjects were aged 10-11 weeks. Across experiments, we found that the effect of MCT consumption on suppressing HFD-induced adiposity is causally related to suppressed HFD-induced hyperphagia. Additionally, we failed to detect an effect of HFD consumption on hippocampal BDNF. Therefore, our findings did not support or oppose the hypothesis that MCT consumption attenuates HFD-induced BDNF deficiency. Future studies should focus on determining the causal relationship between MCT consumption, energy expenditure, and HFD-induced adiposity.

Adipose tissue is one of the most dynamic tissues in the body and is vital for metabolic homeostasis. In the case of excess nutrient uptake, adipose tissue expands to store excess energy in the form of lipids, and in the case of reduced nutrient intake, adipose tissue can shrink and release this energy. Adipocytes are most functional when the balance between these two processes is intact. To understand the molecular mechanisms that drive insulin resistance or conversely preserve the metabolically healthy state in obese individuals, our laboratory performed a screen for differentially regulated adipocyte genes in insulin resistant versus insulin sensitive subjects who had been matched for BMI. From this screen, we identified the type II transmembrane protein tenomodulin (TNMD), which had been previously implicated in glucose tolerance in gene association studies. TNMD was upregulated in omental fat samples isolated from the insulin resistant patient group compared to insulin sensitive individuals. TNMD was predominantly expressed in primary adipocytes compared to the stromal vascular fraction from this adipose tissue. Furthermore, TNMD expression was greatly increased in human preadipocytes by differentiation, and silencing TNMD blocked adipogenic gene induction and adipogenesis, suggesting its role in adipose tissue expansion. Upon high fat diet feeding, transgenic mice overexpressing Tnmd specifically in adipose tissue developed increased epididymal adipose tissue (eWAT) mass without a difference in mean cell size, consistent with elevated in vitro adipogenesis. Moreover, preadipocytes isolated from transgenic epididymal adipose tissue demonstrated higher BrdU incorporation than control littermates, suggesting elevated preadipocyte proliferation. In TNMD overexpressing mice, lipogenic genes PPARG, FASN, SREBP1c and ACLY were upregulated in eWAT as was UCP-1 in brown fat, while liver triglyceride content was reduced. Transgenic animals displayed improved systemic insulin sensitivity, as demonstrated by decreased inflammation and collagen accumulation and increased Akt phosphorylation in eWAT. Thus, the data we present here suggest that TNMD plays a protective role during visceral adipose tissue expansion by promoting adipogenesis and inhibiting inflammation and tissue fibrosis.

Problématique à laquelle répond ce projet de recherche: Les troubles respiratoires obstructifs du sommeil (TROS) comprennent différentes anomalies allant du ronflement chronique au syndrome d’apnée obstructive du sommeil (SAOS). Le SAOS toucherait entre 1 et 5% d’une population pédiatrique générale avec un pic d’incidence entre 2 et 6 ans. Les enfants obèses sont particulièrement atteints avec une prévalence pouvant atteindre 40%. Chez les enfants atteints de malformations crânio-faciales sévères, la prévalence peut atteindre plus de 50%. Les conséquences du SAOS sur le développement de l’enfant peuvent être significatives en l’absence de traitement, tant au point de vue de la croissance que des performances cognitives, du comportement et des paramètres cardio-vasculaires, pulmonaires ou métaboliques. Chez l’adulte, la prévalence du SAOS est estimée, dans la population générale, à 3 à 7% des hommes et à 2 à 5% des femmes d’âge moyen. Cette prévalence serait plus élevée dans certains sous-groupes de la population, notamment les personnes en surpoids ou obèses, chez les femmes enceintes, dans certaines ethnies et chez les personnes âgées. Le SAOS peut entrainer une sur- morbidité cardiovasculaire (hypertension artérielle, accident vasculaire cérébral et infarctus du myocarde) et une augmentation des accidents de travail ou de la circulation imputables à la somnolence. Il est actuellement reconnu que le SAOS pédiatrique et le SAOS de l’adulte ont des causes, des présentations et des conséquences différentes. On ne sait cependant pas si le SAOS de l’adolescent est une poursuite de la forme pédiatrique ou une forme précoce du SAOS de l’adulte. On ne sait pas non plus si certains facteurs de risque sont présents précocement chez l’enfant et persistent jusqu’à l’âge adulte, ou si les deux formes SAOS pédiatrique / adulte ont une étiologie relativement indépendante. Objectifs: Comparer la distribution des caractéristiques morphologiques dento-faciales, fonctionnelles oro- nasales et de l’adiposité entre les membres d’une même famille, (quand à la fois) lorsqu’un enfant et un parent présentent des symptômes de troubles obstructifs du sommeil. Un des membres devra avoir reçu préalablement un diagnostic de SAOS. Type de recherche: Étude transversale observationnelle Méthodologie: Nous avons recruté des enfants afin de planifier un enregistrement du sommeil au CHU Sainte- Justine avec au minimum un de ses parents biologiques directs. Les procédures expérimentales qui ont été utilisées avec chacune de ces familles étaient : • Une évaluation crânio-faciale et fonctionnelle de l’enfant et d'au moins un de ses parents, incluant la prise de photos • Un questionnaire de dépistage du SAOS et un arbre généalogique sur 3 générations • Un enregistrement du sommeil de l’enfant • L'enregistrement du poids et de la taille, de la circonférence du cou, de la circonférence de la taille ainsi que des symptômes liés au SAOS Résultats: Nous avons inclus un groupe de 20 paires (un enfant couplé à un de ses parents). De ce groupe, 13 enfants ont été diagnostiqué du SAOS et 7 en étaient non atteints. Pour ce qui est de l'analyse des questionnaires des enfants, 100% des apnéiques rapportaient une obstruction nasale. Pour les caractéristiques crânio-faciales, 85% de tous les enfants avait la même classification du tonus labial et jugal, 90% de tous les enfants avait avaient la même forme d'arcade maxillaire et mandibulaire et 100% des enfants apnéiques présentaient la même classification de chevauchement dentaire que leur parent. Dans le cas de l'analyse anthropométrique sur photographies, les mesures de la hauteur faciale totale, de la hauteur du tier inférieur et la 2 position antéro-postérieure du maxillaire sont celles qui ont démontrées une certaine tendance d'héritabilité. La mesure N-Gn était plus grande chez les enfants apnéiques, ce qui signifie une hauteur faciale totale plus grande (Cohen d = 1,007). La mesure Sn-Gn était aussi plus grande chez les enfants apnéiques, ce qui signifie un tier inférieur plus long (Cohen d = 1,010). Enfin, l'angle T- N-Sn est plus petit chez les enfants apnéiques (Cohen d = 0,851). Conclusion: L'étude actuelle est une étude pilote constitué d'un échantillon limité. Seul un des deux parents de chaque famille a accepté de participer. Malgré cela, on peut voir une certaine tendance d'héritabilité au niveau du tonus labial et jugal, de la forme des arcades dentaires, de la classification du chevauchement dentaire et de l'obstruction nasale. Des études plus importantes seront cependant nécessaires afin d'obtenir des résultats statistiquement significatifs. / Problem addressed by this research project: Sleep Disordered Breathing (SDB) includes different abnormalities ranging from chronic snoring to obstructive sleep apnea syndrome (OSAS). OSAS would affect between 1 and 5% of a general pediatric population with a peak incidence between 2 and 6 years old. Obese children are particularly affected with a prevalence of up to 40%. In children with severe craniofacial malformations, the prevalence can reach more than 50%. The consequences of OSAS on child development can be significant in the absence of treatment, both in terms of growth and cognitive performance, behavior and cardiovascular, pulmonary or metabolic parameters. In adults, the prevalence of OSAS is estimated, in the general population, at 3 to 7% of men and 2 to 5% of middle-aged women. This prevalence would be higher in certain subgroups of the population, in particular overweight or obese people, in pregnant women, in certain ethnic groups and in the elderly. OSAS may lead to increased cardiovascular morbidity (arterial hypertension, stroke, myocardial infarction), and an increase in work or traffic accidents attributable to drowsiness. It is currently recognized that pediatric OSAS and adult OSAS have different causes, presentations and consequences. However, it is not known whether adolescent OSAS is a continuation of the pediatric form or an early form of adult OSAS. It is also unclear whether certain risk factors are present early in childhood and persist into adulthood, or whether the two pediatric/adult forms of OSAS have a relatively independent etiology. Aims: To compare the distribution of dentofacial morphological, oronasal functional characteristics and adiposity between members of the same family, when both child and parent present with symptoms of SDB. One of the members must have previously received a diagnosis of OSAS. Type of research: Observational cross-sectional study Methodology: We recruited children scheduled for sleep recording at CHU Sainte-Justine as well as at least one of their direct biological parents. The experimental procedures that were used with each of these families were: • A craniofacial and functional assessment of the child and at least one of his parents, including taking photos • An OSAS screening questionnaire and a 3-generation family tree • A sleep recording of the child • Records of weight and height, neck circumference, waist circumference and symptoms related to sleep apnea were also collected Results: We included a group of 20 pairs (a child coupled to one of his parents. Of this group, 13 children were diagnosed with OSAS and 7 were unaffected. Regarding the analysis of the children's questionnaires, 100% of apneic patients report nasal obstruction. For craniofacial features, 85% of all children had the same labial and jugal tone classification, 90% of all children had the same maxillary and mandibular arch shape, and 100% of apneic children had the same classification of the dental crowding as their parent. In the case of the anthropometric analysis on photographs, the measurements of the total facial height, the height of the lower third and the anteroposterior position of the maxilla are those that demonstrated a certain trend. The N-Gn measurement was greater in children with apnea, signifying greater total facial height (Cohen d = 1.007). The Sn-Gn measure was also greater in children with apnea, meaning one lower third longer (Cohen d = 1.010). Finally, the T-N-Sn angle is smaller in apneic children (Cohen d = 0.851). 5 Conclusion: The current study is a pilot study consisting of a limited sample. Only one parent from each family agreed to participate. Despite this, we can see a certain trend of heritability at the level of the labial and jugal tone, the shape of the dental arches, the classification of the dental crowding and the nasal obstruction. However, larger studies will be needed to obtain statistically significant results.

Obesity has been related to a greater incidence of more aggressive, advanced stage prostate cancer. It is expected that serum adipokines related to obesity will promote a more aggressive phenotype in PC cells in vitro. Patient serum (n = 80) was obtained for analysis and divided into four patient groups based on obesity and prostate cancer status. Characteristics of serum-treated PC cells in vitro were measured. In a separate set of analyses, LNCaP and PC3 cells were treated with adiponectin and resistin in vitro, and cell characteristics were analyzed. Serum from obese PC patients induces greater amounts of cell migration and lower amounts of cell proliferation and invasion in vitro. Exogenous treatment of adiponectin on PC cells in vitro does not affect cell migration or invasion. However, adiponectin modulates cytosolic protein levels of soluble β-catenin and GSK-3β, indicating that its mechanism of action may be through the Wnt signalling pathway.

Les cytokines, produites lors de l’activation du système immunitaire, ont la capacité d’agir au niveau du système nerveux central et d’induire diverses altérations comportementales. Lorsque l’activation du système de l’immunité innée devient chronique, ces altérations comportementales peuvent évoluer en véritables symptômes neuropsychiatriques. La physiopathologie des symptômes neuropsychiatriques qui se développent dans un contexte d’inflammation chronique à bas bruit, c’est-à-dire caractérisé par une activation chronique des processus immunitaires mais à un niveau relativement faible, est peu connue et reste à déterminer. L’implication de l’inflammation chronique à bas bruit dans les symptômes de fatigue et les altérations cognitives constitue l’élément d’étude principal de ce travail de thèse. Les troubles métaboliques, tels que l’obésité et le diabète de type 2, sont de bons modèles pour une telle étude. Ces deux pathologies sont en effet caractérisées par une inflammation chronique à bas bruit qui proviendrait, au moins en partie, du tissu adipeux. De plus, la fatigue et les altérations cognitives sont fréquentes chez les patients souffrant de troubles métaboliques. Compte tenu du rôle connu de l’inflammation dans la physiopathologie de ces altérations comportementales, leur développement dans des contextes de troubles métaboliques pourrait également être lié à l’activation chronique à bas bruit de processus inflammatoires. Différents objectifs ont été définis pour tester cette hypothèse : 1) caractériser et spécifier les symptômes de fatigue et les altérations cognitives chez des patients diabétiques ou obèses ; 2) évaluer la relation entre inflammation systémique et état inflammatoire du tissu adipeux ; 3) étudier l’association de l’inflammation chronique à bas bruit avec les symptômes de fatigue et les altérations cognitives des patients souffrant de troubles métaboliques. Nos résultats indiquent que la fatigue, en particulier la fatigue générale et physique, représente une caractéristique fondamentale des troubles métaboliques. Des perturbations cognitives, se traduisant par un ralentissement psychomoteur dans un test de temps de réaction ainsi qu’une altération de performance dans une tâche de planification spatiale, ont également été décelées chez les patients diabétiques de type 2, particulièrement ceux sous insulinothérapie, et chez les patients obèses. Des altérations mineures étaient également mesurées dans une tâche d’empan spatial rétrograde chez les patients obèses. En ce qui concerne les données biologiques, nos résultats indiquent diverses associations entre l’inflammation systémique et l’expression des marqueurs inflammatoires (cytokines inflammatoires, dont le MCP1, et marqueurs des cellules T) dans le tissu adipeux viscéral des patients obèses. De façon intéressante, l’inflammation systémique à bas bruit était associée aux dimensions de fatigue (générale, mentale, réduction des activités et de la motivation) et aux altérations de performance dans les tests ciblant les fonctions exécutives. Dans l’ensemble, ces résultats supportent l’hypothèse de l’implication des macrophages et des lymphocytes T du tissu adipeux dans l’état inflammatoire systémique associé à l’obésité. Il suggère en outre que l’inflammation systémique à bas bruit pourrait participer au développement de la fatigue et des altérations cognitives chez les patients souffrant de troubles métaboliques. Ce travail de thèse offre une caractérisation précise des symptômes de fatigue et des altérations cognitives associées aux troubles métaboliques. En outre, ce travail apporte d’importantes informations sur les relations de l’inflammation chronique à bas bruit avec ces symptômes, et permet d’affiner les hypothèses relatives à l’implication de processus inflammatoires dans la physiopathologie de ces altérations. / Cytokines produced during the activation of the immune system have the ability to act within the central nervous system and to induce a large number of behavioral alterations. When the activation of immune system becomes chronic and unregulated, these behavioral alterations may lead to the development of neuropsychiatric symptoms. The pathophysiology of neuropsychiatric symptoms that develop in conditions of chronic low-grade inflammation context (i.e., characterized by a chronic but low activation of inflammatory processes), remains unknown. The main aim of this thesis was to investigate the involvement of low-grade inflammation in the development of fatigue symptoms and cognitive alterations in patients with metabolic disorders including obesity and type 2 diabetes. These conditions are characterized by a chronic low-grade inflammatory state, manifesting by higher blood concentrations of inflammatory factors. This inflammatory state would originate, at least partially, from the adipose tissue. Moreover, fatigue symptoms and cognitive alterations are common in metabolic disorders. Given the role of inflammation in the physiopathology of these symptoms, their development could also rely on chronic low-grade inflammatory processes. Several objectives were defined to test this hypothesis: 1) to characterize fatigue symptoms and cognitive alterations in obese and diabetic patients; 2) to assess the relationship of systemic inflammation with the inflammatory state of the adipose tissue; and 3) to investigate the association of low-grade inflammation with fatigue symptoms and cognitive alterations in patients with metabolic disorders. Fatigue symptoms and cognitive function were respectively assessed using the multidimensional fatigue inventory (MFI) and the neuropsychological tests automated battery CANTAB in diabetic patients (type 1 and type 2) and in obese patients before and after bariatric surgery. A control group was included for each model (obesity and type 2 diabetes). Circulating concentrations of inflammatory markers, as well as expression of inflammatory markers in the visceral adipose tissue of obese patients, were measured. Our results indicate that fatigue symptoms, especially in the dimensions of general and physical fatigue, represent fundamental characteristics of patients suffering from metabolic disorders. In addition, cognitive alterations (psychomotor slowing and alterations in spatial planning performance) were measured in type 2 diabetic patients, more particularly those under insulin treatment, and in obese patients. Slight alterations in the test of backward spatial span were measured in obese patients. With respect to biological data, our results indicate significant relationships between systemic inflammation and inflammatory markers (inflammatory cytokines, including MCP1, and T-cell markers) in the visceral adipose tissue of obese patients. Interestingly, chronic low-grade inflammation was associated with fatigue symptoms (general fatigue, mental fatigue, reduced activity and motivation) and performance alterations in tests assessing executive functions. Altogether, these data support the hypothesis of the involvement of the adipose macrophages and T lymphocytes in the systemic inflammatory state associated with obesity. Moreover, these results suggest that systemic low-grade inflammation associated with metabolic disorders may contribute to the physiopathology of fatigue and cognitive alterations in these conditions. In conclusion, these studies provide a precise characterization of fatigue symptoms and cognitive alterations associated with metabolic disorders, such as obesity or type 2 diabetes. In addition, this thesis work gives interesting information about the relationships of chronic low-grade inflammation and fatigue and cognitive symptoms, and refines hypotheses regarding the involvement of inflammatory processes in the physiopathology of these symptoms in patients with diabetes or obesity.

Durante a vida intrauterina, o desenvolvimento do embrião e do feto é suscetível a mudanças ambientais que podem alterar o fenótipo do indivíduo na vida pós-natal. Eventos que ocorrem durante períodos críticos de rápida divisão celular, nos quais são formados os diversos órgãos e tecidos, podem alterar a estrutura e função de sistemas orgânicos gerando consequências precoces (baixo peso ao nascimento) e tardias (doenças na vida adulta). Os protocolos experimentais da maior parte dos estudos sobre a programação fetal reduz o tamanho da ninhada logo após o nascimento. Essa abordagem dificulta a interpretação e reprodutibilidade dos resultados observados. O objetivo deste estudo foi determinar se a pressão sanguínea, o metabolismo de carboidratos e gasto energético em proles adultas é influenciado pelo tamanho da ninhada. Ratas Wistar foram alimentadas com ração padrão ad libitum e foram acasaladas com ratos machos com 12 semanas de idade. Após o nascimento, a prole foi dividida em três grupos: tamanho da ninhada sem redução (Gc), proles reduzido a oito filhotes (G8) e proles reduzidos a quatro filhotes (G4). Ao fim de 12 semanas de idade, o peso corporal, pressão arterial, consumo de ração, glicemia, insulina, colesterol e triacilgliceróis, massa de tecido adiposo marrom, índice de adiposidade, massa renal e cardíaca foram determinados. O peso corporal, índice de adiposidade, glicemia, nível de insulina e índice HOMA foram maiores em machos e fêmeas no grupo G4 do que nos grupos G8 e Gc. No entanto, o consumo de ração foi menor no grupo G4. A pressão arterial foi maior no grupo Gc em machos e fêmeas. Em resumo, a redução do tamanho da ninhada está relacionada com a obesidade, resistência à insulina e possíveis alterações no gasto energético na prole adulta / During intrauterine life, the developing fetus is susceptible to environmental changes that can alter the phenotype of the individual in postnatal life. This phenomenon is called fetal programming. Events that occur during critical periods of rapid cell division may alter the structure and function of organ systems, resulting in consequences both early (low birth weight) and late (diseases in adulthood) in life. The experimental protocols of most of the studies on fetal programming involve a reduction in litter size soon after birth. This approach hampers the interpretation and reproducibility of the observed results. The purpose of this investigation was to determine if blood pressure, carbohydrate metabolism and energy expenditure in adult offspring are influenced by litter size. Female Wistar rats were fed standard rat chow ad libitum and were mated with male rats at 12 weeks of age. After birth, the offspring were divided into three groups: unchanged litter size (GU), culled to eight neonates (G8) and culled to four neonates (G4). At 12 weeks of age, the body weight; blood pressure; food intake; glucose, insulin, cholesterol and triacylglycerol levels; brown adipose tissue mass; adiposity index; renal mass; and cardiac mass were determined. The body weight, adiposity index, glucose level, insulin level and HOMA index were higher in males and females in the G4 group than in the G8 and GU groups. However, food consumption was lower in G4 males. The blood pressure was higher in the GU group. In summary, a small litter size is related to obesity, possible alterations in energy expenditure and insulin resistance in adult offspring

INTRODUÇÃO: A obesidade mórbida tornou-se um importante problema de saúde pública. A medida de massa corporal não é capaz de identificar deficiências ou excessos dos diferentes componentes corporais, surgindo a necessidade de se avaliar a composição corporal. Não há consenso sobre o melhor método para esse fim em obesos mórbidos. O Índice de Adiposidade Corporal (IAC) foi proposto para ser um método simples e preciso para uma população de diversificada quantidade de gordura corporal (GC). OBJETIVO: Avaliar a eficácia do IAC em determinar GC de adultos com obesidade mórbida. MÉTODOS: O IAC foi comparado à Bioimpedância (BIA) em 240 adultos obesos mórbidos (Grupo 1= G1), uma equação específica para determinar GC em obesidade mórbida foi desenvolvida e, posteriormente, validada em outra amostra de 158 indivíduos (Grupo 2 = G2). RESULTADOS: Observou-se diferença significativa entre os dois métodos (p=0,039). A quantidade média de GC no G1 foi 52,3±6,1% segundo a BIA e 51,6±8,1% segundo o IAC, com uma diferença de 0,6±5,1% entre os métodos. Algumas variáveis, como gênero, RCQ e gravidade da obesidade confundiram o IAC. Para minimizar esses erros uma equação (Índice de Adiposidade Corporal Modificado = IACM) foi desenvolvida por meio de regressão linear (IACM% = 23,6 + 0,5 x (IAC); somar 2,2 se IMC >= 50kg/m2 e 2,4 se RCQ >= 1,05). A equação foi aplicada no G2 e possibilitou a redução da diferença entre os métodos (1,2±5,9% para 0,4±4,0%) e o fortalecimento da correlação entre eles (0,6 para 0,7). CONCLUSÕES: O IAC apresenta limitações para determinar porcentagem de gordura corporal de obesos mórbidos, já a equação sugerida (IACM) foi eficaz, não se apresentando significativamente diferente da Bioimpedância e corrigindo as limitações anteriormente apresentadas pelo IAC / BACKGROUND: Morbid obesity has become a public health problem. As body mass is not able to identify deficiencies or excesses of body components, the need to assess body composition emerged. There is no consensus of the best method to measure body composition in morbidly obese adults and a simple, accurate, reproducible and inexpensive method is desirable. The Body Adiposity Index (BAI) has been proposed to be a simple and accurate method for a population with a diverse amount of body fat (BF). OBJECTIVE: Evaluate the efficacy of BAI in determining BF of morbid obese adults. METHODS: BAI was compared to bioimpedance (BIA) in 240 morbidly obese adults (Group One= G1) and a specific equation for morbid obesity has been developed to determine BF and then validated on another sample of 158 subjects (Group Two= G2). RESULTS: There was a significant difference between the two methods (p=0,039). The average amount of BF in G1 was 52.3±6.1%, according to BIA and 51.6±8.1% according to BAI, with a difference of 0.6±5.1% between methods. Some variables, such as gender, WHR and severity of obesity mistook BAI. To minimize these errors an equation (Modified Body Adiposity Index = MBAI) was developed by linear regression (MBAI% = 23.6 + 0.5 x (BAI); add 2.2 if BMI >= 50kg/m2 and 2.4 if WHR >= 1.05). The equation was applied to G2 and resulted in a reduction in the difference between methods (1.2±5.9% to 0.4±4.12%) and strengthening of the correlation between them (0.6 to 0.7). CONCLUSIONS: BAI has limitations in determine BF in morbid obesity. The suggested equation (MBAI) was effective for predicting body fat in morbid obese adults; MBAI wasn\'t significant different from BIA and was able to correct BAI limitations