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Au Canada, en 2004, 2,7% des adultes étaient considérés comme étant des obèses sévères, et ce, malgré toutes les recherches et la prévention pour contrer le gain de poids. L'obésité sévère est bien plus qu'un simple problème d'esthétique. Cette condition est un précurseur de plusieurs comorbidités qui diminuent la qualité et l'espérance de vie. En ce moment, le seul traitement efficace et durable est la chirurgie bariatrique. Cette procédure engendre des changements non seulement corporels, mais également métaboliques et physiologiques. Les mécanismes par lesquels celle-ci parvient à une amélioration marquée des comorbidités ne sont pas encore bien compris. Une des hypothèses serait les changements engendrés sur les adipokines, des molécules libérées par le tissu adipeux. La visfatine et l'apeline sont toutes deux des adipokines reliées au métabolisme de l'insuline et aux marqueurs inflammatoires. Ces deux adipokines ont récemment été découvertes et leur fonctionnement reste encore inconnu. Savoir comment ces deux adipokines réagissent au changement drastique de composition corporelle pourrait amener à une piste dans la compréhension des comorbidités, de leur résolution ainsi que dans le développement d'agents pharmaceutiques futurs pouvant améliorer les comorbidités, en étant moins drastiques que la chirurgie bariatrique. Dans ce mémoire, l'impact aigu et chronique de la dérivation biliopancréatique avec commutation duodénale sur les concentrations plasmatiques de visfatine et d'apeline sera évalué. Les patients ayant subi une DBP-CD (groupe DBP-CD) ont été comparés avec un groupe avec obésité sévère (groupe témoin). Des mesures anthropométriques et des échantillons sanguins ont été effectués avant, au jour 1 et 5 et à 6 et 12 mois après la chirurgie dans le groupe DBP-CD. Il y a eu 70 sujets dans le groupe DBP-CD et 28 dans le groupe témoin. Un an après la chirurgie, on retrouve une réduction du poids corporel (136,4 ± 27,6 vs. 85,9 ± 18,5 kg, p<0,001). La concentration de visfatine a diminuée un jour après la chirurgie (18,82 ± 7,36 vs. 16,13 ± 5,56 ng/ml; p=0,001) et la concentration d'apeline 5 jours après la chirurgie (0,55 ± 0,33 vs. 0,50 ± 0,28 ng/ml; p=0,040). Dans le groupe témoin, il n'y a eu aucun changement significatif dans tous les paramètres. En conclusion, on observe une diminution aiguë des concentrations de visfatine et d'apeline après la DBP-CD. La perte de poids à long terme n'a eu aucun impact sur ces concentrations.

Le diabète gestationnel (DG) est un trouble de la tolérance glucidique de gravité variable, survenant ou diagnostiqué pour la première fois pendant la grossesse, quel que soit le traitement nécessaire et son évolution après l’accouchement. Il est associé, à court et à long terme, à un ensemble de complications ou pathologies tant chez la mère que chez l’enfant. Nous avons étudié le rôle des cytokines, des adipokines, du statut anti-oxydant et des facteurs de croissance au cours du diabète gestationnel et de la macrosomie. Notre étude a montré que le diabète gestationnel et la macrosomie sont associés à une perturbation du métabolisme lipidique et une altération des statuts antioxydant et immunitaire. Le DG était lié à une diminution de l’adiponectine et des cytokines Th1 et une augmentation de la leptine et des cytokines inflammatoires alors que la macrosomie est associée à une augmentation des cytokines Th1 et une diminution de toutes ces hormones relatives à l’obésité (IL-6, TNF-α, leptine et adiponectine). Plusieurs altérations observées à la naissance dans le métabolisme des carbohydrates et des lipides chez les enfants issus de mères diabétiques persistent encore à l’âge adulte. Il semble que la programmation in utero au cours du diabète gestationnel crée une ‘‘mémoire métabolique’’ qui est responsable de l’obésité et des altérations chez les nouveau-nés macrosomiques. Selon les régressions linéaires multiples incrémentielles que nous avons établies, il semble que les facteurs de croissance qui influencent l’augmentation du poids fœtal sont : PDGF du côté maternel et FGF2 des deux côté maternel et fœtal. / Gestational diabetes mellitus (GDM) is defined as ‘carbohydrate intolerance of variable severity with onset or first recognition during pregnancy’, irrespective to necessary treatment and its evolution in the post partum. GDM is associated with a number of complications/ pathologies both in mother and in their newborns, with short and long-term. In this study, we investigated the role of cytokines, adipokines and antioxidant status during GDM and macrosomia. Our study has demonstrated that these pathologies are associated with a perturbation in lipid metabolism, and antioxidant and immune status. GDM is linked to the down-regulation of adiponectin along with Th1 cytokines and upregulation of leptin and inflammatory cytokines whereas macrosomia was associated with the up-regulation of Th1 cytokines and the down-regulation of the obesity-related agents (IL-6, TNF-α, leptin and adiponectin). Several alterations observed at birth in carbohydrates and lipids metabolism in the children born to diabetic mothers, still persist at the adulthood. It seems that in utero programming during diabetic pregnancy creates a ‘‘metabolic memory’’ which is responsible for the development of obesity and physiological anomalies in macrosomic offspring. According to multiple linear regressions incremental that we established, it appears that growth factors that influence the increase of foetal weight are: PDGF in mother's side and FGF2 in maternal and foetal side.

Cette thèse présente les adaptations spécifiques des hibernants ‘food-storing’ qui s’alimentent au cours de l’hibernation, et les conséquences de la qualité du régime alimentaire sur leur cycle annuel. Tandis que les espèces ‘fat-storing’ jeûnent pendant toute l’hibernation, les ‘food-storing’ alternent jeûnes courts et réalimentations. L’adiponectine stimulerait la lipolyse pendant l’hibernation contribuant ainsi à la cétogenèse. Le maintien d’un système digestif fonctionnel conduisant à la sécrétion d’incrétines, permet l’absorption optimale de nutriments lors des courtes euthermies inter-torpeurs. Une absorption accrue de glucose en particulier permettrait de restaurer la glycémie et les réserves de glycogène. Par ailleurs, un régime appauvri en protéines et enrichi en lipides induit un engraissement augmenté en période pré-hibernatoire provoquant une moindre utilisation de la torpeur donc une perte de masse accrue lors de l’hibernation, et une baisse du succès reproducteur. / This thesis presents the specific adaptations of food-storing hibernators that feed during hibernation, and the impact of diet quality on their annual cycle. In contrast to the fat-Storing species which fast during hibernation, the food-storing presents metabolic responses to an alternation of short fasting phases and hyperphagia. These responses involve one hand use of fat reserves during hibernation contributing to ketogenesis, which would be induced by adiponectin. On the other hand, maintaining a functional digestive system leading to the secretion of incretins, permits optimal nutrient absorption in the short inter-torpor euthermia. Increased glucose uptake in particular would restore body reserves to spare. Moreover, a lean protein diet enriched in fat and induces increased in body mass in pre-hibernation period causing reduced use of torpor thus an increased loss of mass during hibernation, and decreased reproductive success.

Les omégas trois ont un bénéfice prouvé dans la prévention de maladie cardiovasculaire et l’inflammation. Un apport optimal peut être réalisé avec des modifications diététiques simples permettant d’avoir un enrichissement des membranes cellulaires et un effet métabolique. Le tissu adipeux de part son rôle important dans la genèse du syndrome métabolique semble être une cible importante du traitement par oméga trois. Les patients avec une maladie rénale chronique (MRC) ont un risque cardiovasculaire accru et cumulent les perturbations métaboliques comme le syndrome métabolique et un état micro inflammatoire. Des doses supra physiologiques d’oméga trois ont été utilisés dans le passé dans des études de prévention rénale ou traitement de dyslipidémie. Or l’effet métabolique en fonction de la dose d’oméga 3 n’est pas connu. En accord, avec les études chez le sujet sain, en fonction de la dose administrée, les omégas 3 ont un impact différent métabolique et sur l’expression génique. Des études complémentaires sont nécessaires pour vérifier la faisabilité et l’impact métabolique d’une modification de régime afin de diminuer le rapport n-6/n-3, ainsi que l’effet à long terme des omégas trois chez ces patients. Par ailleurs, les mécanismes impliqués dans les différences de dose réponse devront être caractérisés sur un modèle animal / Omega 3 fatty acids play an important modulatory role in metabolic and inflammatory responses, the progression of atherosclerosis and gene expression. Recent studies suggest their beneficial impact on adipocyte morphology and function. Chronic kidney disease (CKD) patients have an increased cardiovascular morbi-mortality and suffer from a cluster of metabolic disorders. On the basis of previous studies there are reasons to suggest that omega 3 supplementation may offer a host of benefits to CKD patients. Unfortunatly, published studies on the effect of such supplementation are characterized by supra physiological omega 3 doses, that may be difficult to implement for extended periods in one hand and in the other hand the metabolic effect of different doses of omega 3 hasn’t been studied in detail. Simple dietary modifications can help achieve the recommended n-6/n-3 ratio in healthy subjects. In CKD patients supplementation with n-3 shows a differential dose response effect. Further studies are required to test the faisability and metabolic impact of dietary modifications in order to decrease n-6/n-3 ratio and to assess the long term effect of omega supplementation in CKD patients. Finally the molecular pathways implicated in this differential dose response should be assessed in animal models

Obesity affects about 520 million people world-wide and more recently studies have shown that fat cells produce proteins called adipokines which have various influences on the human metabolism and has helped to change the perspectives of researchers on the concept of the adipose tissue being just a store of energy. As a result of this, adipokines have been reported to represent a connection between obesity and cardiovascular diseases (CVD) and diabetes mellitus. The concentrations and the bases of the effects of the adipokines in beta cell failure of diabetes mellitus and endothelial cell dysfunction of cardiovascular diseases are still not fully understood. The effect of leptin and adiponectin, which are two adipokines with opposing effects, has been explored in this study. In the present study, therefore, the concentrations of leptin and adiponectin with significant effect on beta cell and endothelial cell function and the basis of these functions were explored. Also, attempts were made in the present study to correlate the concentrations of leptin and adiponectin with possible clinical pointers to complications. In order to achieve this, beta cells (BTC) were grown, made into pseudo-islets (which are said to produce more insulin) and treated with various concentrations of leptin and adiponectin and cells assayed for insulin and amylin (to investigate the role of amylin in insulin secretion). Also the cells were collected and mRNA extracted from these cells, reverse transcription PCR carried out to find out the role of protein phosphatase 1 (PP-1) in the effect of leptin on insulin secretion. PP-1 is a substrate that increases insulin secretion by allowing calcium influx into the cell and is said to be blocked by leptin). Leptin at 500ng/ml was found to significantly (p<0.05) inhibit the secretion of insulin and the expression of PP1 gene, thus supporting this as a basis for the effect of leptin on insulin secretion. Adiponectin however increased insulin secretion significantly but was not as consistent in its effect as leptin was in inhibiting insulin secretion. In order to explore the role of adipokines in cardiovascular diseases, EAHY human endothelial cells were cultured and treated with various concentrations of adiponectin and leptin both individually and in combinations and cells collected and mRNA extracted in order to carry out a reverse transcription PCR for the expression of angiogenic (TIMP2, TIMP3 and MMP2) genes and atherosclerotic (LPA and LPL) genes. Leptin (1nM) was shown to increase the expression of atherosclerotic and angiogenic genes while adiponectin (100nM) inhibited the expression of the atherosclerotic and angiogenic genes. A combination of leptin and adiponectin caused a reduction in the stimulatory effect of leptin on the expression of atherosclerotic and angiogenic genes. This shows that leptin may predispose to CVD while adiponectin reduces the risk of CVD. The clinical part of this study involved recruiting 150 patients with diabetes after the ethical approval for the clinical study was granted. The data collected from the patients included their age, sex, race, and physical parameters like the body mass index (BMI). Also blood samples were collected to measure the clinical indicators for CVD and renal function such as cholesterol, HDL levels, eGFR, albumin levels and their retinopathy status checked as these are the common complications seen in diabetic patients. The blood samples were also assayed in the laboratory for leptin and adiponectin levels and the leptin, adiponectin and the leptin/adiponectin ratio (LAR) were then correlated with the laboratory determinants of CVD, renal and retinopathy risks. It was found that the LAR and the leptin levels correlates significantly with the BMI, while the leptin levels were significantly correlated with the risk of nephropathy in diabetic patients while adiponectin levels correlated significantly with a reduced risk for developing CVD. The role of the enzymes in the leptin and adiponectin signaling pathway was also explored and it was discovered that ERK, P38 and AMPK all had roles in the effect of leptin and adiponectin on the expression of atherosclerotic and angiogenic genes. These data indicate that leptin and adiponectin play significant roles in the beta cell and endothelial cell function and are links between obesity and CVD and diabetes mellitus.

Obesity is a multi-factorial metabolic disease, resulting in increased adipose tissue acquisition by the host. This disease increases the risk for developing co-morbidities, including Metabolic Syndrome and other disorders such as breast cancer. Obesity, and particularly abdominal obesity, is characterised by metabolic changes, including chronically elevated insulin concentrations and aberrant secretion of cytokines released from fat tissue, called adipokines. Epidemiologically, the risk of developing postmenopausal breast cancer is increased in obese individuals. The molecular link between obesity and breast cancer however is not well understood. The study presented here aimed at identifying the molecular mechanisms involved in this link, by testing the hypothesis that high insulin concentration and certain adipokines may promote breast cancer progression and/or breast cancer aetiology. A cell culture system of breast cancer cells and breast epithelial cells was employed to investigate changes in cell proliferation, activation of cell signalling pathways, cell cycle progression and apoptosis after treatment with insulin, leptin, TNF-α, adiponectin and IL-6. In MDA-MB-231 breast cancer cells, insulin treatment did not affect cell proliferation, cell cycle or apoptosis. Conversely, IR-phosphorylation, AKT-phosphorylation and ERK1/2-phosphorylation were all significantly increased. Microarray analysis indicated several important changes in gene expression with insulin treatment. Leptin treatment increased proliferation by 21%. Additional analyses of the effect of leptin indicated that neither the PI3-kinase pathway nor the MAP-kinase pathway was involved in mediating this effect. Treatment with TNF-α increased apoptosis, but did not affect cell proliferation or activation of cell signalling pathways. In MCF-10A breast epithelial cells, cell proliferation increased after insulin treatment by 180%. IR-phosphorylation, AKT-phosphorylation and ERK1/2 phosphorylation were all significantly increased while early apoptosis decreased after insulin treatment. Analysis of cell cycle however did not indicate a change in progression. Microarray analysis indicated that insulin treatment may increase expression of genes related to cancer growth. Leptin treatment increased cell proliferation and also increased ERK1/2-phosphorylation, while AKT-phosphorylation was not affected. Leptin did not change cell cycle progression. TNF-α treatment increased cell proliferation and also increased ERK1/2 phosphorylation, while AKT-phosphorylation was not changed. TNF-α treatment tended to increase apoptosis, the change however was not statistically significant. In SK-BR-3 breast cancer cells, cell proliferation did not change after insulin treatment. IR-phosphorylation and AKT-phosphorylation increased after insulin treatment, while ERK1/2-phosphorylation decreased. Gene expression of cyclin D and cyclin E increased with insulin treatment, while apoptotic rate and cell cycle profile were also not affected. Cell proliferation increased by 115% after treatment with 100 ng/ml leptin. ERK1/2-phosphorylation however decreased, while AKT-phosphorylation tended to increase, but the change was not statistically significant. Cell cycle profile was not affected by leptin treatment, G1-phase however tended to increase, but the change was again not statistically significant. Cell proliferation increased by 59% after 48 h treatment with 10 ng/ml TNF-α. AKT-phosphorylation and ERK1/2-phosphorylation increased with TNF-α treatment. Cell cycle analysis showed a decrease in S-phase and G2-phase, indicative of a decrease in cell cycle progression. These results indicate that none of the examined obesity-related factors is convincingly identified as the main molecular link between obesity and postmenopausal breast cancer. Conversely, all treatments affected each of the cell lines in, at least, one of the examined aspects. This indicates that many of the obesity-related factors may affect breast cancer and that a single breast tumour may utilise a unique combination of those factors to promote growth. All treatments increased proliferation in MCF-10A breast epithelial cells, with additional analysis generally supporting growth promotion. Insulin treatment particularly increased cell proliferation, while leptin and TNF-α increased MAP-kinase signalling. This may indicate that insulin and adipokines may have a higher impact on breast cancer aetiology than on breast cancer progression.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Alcoholic Fatty Liver Disease (AFLD) is caused by excessive alcohol consumption and is a leading cause of liver related mortalities, with currently no treatments available. The goal of this project was to establish the effect of alcohol consumption on adipose tissue-derived secreted factors, adiponectin and C1q TNF Related Proteins 1-3 (CTRP1-3). We propose that excessive alcohol consumption will reduce circulating levels of adiponectin and CTRPs 1-3. Mice were fed a Lieber-Decarli control or alcohol diet for 10-days with a gavage (NIAAA model) or 6-weeks with no gavage (chronic model). Serum and adipose tissue were collected and CTRPs 1-3 and adiponectin levels were examined by immunoblot analysis. Our results indicate that long-term alcohol consumption effects adipokine secretion in a sex specific manner. Further research will be needed to explore the physiological relevance of these findings, to determine if these changes are beneficial to combat the negative effects of excessive alcohol consumption.