Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2009-2010 / Le tissu adipeux, autrefois perçu comme un organe inerte voué au stockage de gras est maintenant reconnu comme un organe sécrétant de nombreux facteurs, nommés adipokines. Certains de ces facteurs – on en compte plusieurs dizaines – influencent le métabolisme de la même façon que des hormones plus connues comme l’insuline ou le glucagon peuvent le faire. Ce mémoire porte sur l’étude de deux adipokines en particulier, la protéine stimulant l’acylation (ASP) et la résistine, en relation avec l’obésité et ses co-morbidités. Le premier projet visait à étudier les adaptions du métabolisme hépatique dans des modèles murins ne possédant pas de voie de signalisation fonctionnelle de l’ASP, des modèles résistants à l’obésité. Cette étude a permis de démontrer l’absence de stéatose hépatique et de surproduction de lipoprotéines chez ces souris en plus de mettre en évidence une utilisation altérée des substrats énergétiques par le foie. Le second projet visait à étudier les corrélations entre la résistine plasmatique et de nombreux paramètres liés au syndrome métabolique dans une population d’enfants et d’adolescents chinois. Cette étude a démontré que la résistine n’y est pas corrélée avec la résistance à l’insuline, mais qu’elle y est retrouvée en plus grande concentration s’il y a présence d’obésité centrale. Globalement, ce mémoire met en lumière tant de façon fondamentale que clinique les implications physiologiques des deux adipokines étudiées – l’ASP et la résistine – et clarifie leur potentiel thérapeutique. / Adipose tissue has been recently recognized to function as an endocrine organ in addition to its fat storage capacities. Adipose tissue secretes a number of factors named adipokines. Some of these hormones influence metabolism similarly to other well-known factors such as insulin and glucagon. This thesis is the result of studies done on two particular adipokines, acylation stimulating protein (ASP) and resistin, as well as their relationship with obesity and its co-morbidities. The aim of the first project was to understand the adaptations of hepatic metabolism in murine models with ASP-C5L2 pathway deficiencies, models that are also obesity resistant. This study demonstrated the absence of hepatic steatosis or lipoprotein overproduction in these mice in addition to showing signs of altered substrate use by the liver. The second study evaluated correlations between plasma resistin and several parameters related to the metabolic syndrome in a population of Chinese children and adolescents. This study demonstrated that resistin does not correlate with insulin resistance, but that circulating levels of resistin are increased in the presence of central obesity. Globally, this thesis shows, from both a clinical and basic science perspective, the physiological implications of the two adipokines studied – ASP and resistin – and clarifies their therapeutical potential.

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2008-2009 / L'objectif de cette thèse était de mieux comprendre l'association entre les androgènes et la distribution régionale des graisses chez l'homme et la femme. Les résultats obtenus ont permis de clarifier les effets des androgènes sur le métabolisme des lipides et la différenciation adipocytaire de cultures primaires isolées à partir d'échantillons de tissu adipeux abdominal humain. Nous avons également étudié les facteurs responsables des discordances entre les différentes études chez la femme au niveau des associations entre les concentrations circulantes d'androgènes et la distribution régionale des graisses. Nous avons concentré nos efforts à étudier les enzymes impliquées dans le métabolisme local des androgènes dans le tissu adipeux abdominal sous-cutané et omental, chez l'homme et la femme. Parmi ces enzymes, nous avons déterminé que trois enzymes de la famille des aldocéto reductases 1C (AKR1C1, 2 et 3) pourraient avoir un rôle particulièrement important dans la modulation des concentrations locales d'androgènes actifs et pourraient potentiellement être impliquées dans l'étiologie de l'obésité viscérale. Les résultats obtenus permettent également de suggérer un lien entre le métabolisme local des glucocorticoïdes et le métabolisme local des androgènes par les enzymes AKR1C. / The objective of this thesis was to better understand the relationship between androgens and body fat distribution in men and women. The results obtained allowed to clarify the effects of androgens on lipid metabolism and adipocyte differentiation in primary cultures isolated from human abdominal adipose tissue. We also investigated the discrepancies observed in studies which have examined associations between circulating androgen levels and body fat distribution in women. We focused our efforts on the study of steroid-converting enzymes involved in local androgen metabolism in abdominal subcutaneous and omental adipose tissue, in men and women. We observed that three enzymes from the aldoketo reductase 1C family (AKR1C1, 2 and 3) may be of particular importance in the modulation of active androgen concentrations on a local basis and may also be involved in the development of visceral obesity. The results also suggest a potential crosstalk between local glucocorticoid and androgen metabolism by AKR1C enzymes.

Many studies have shown that peroxisome-proliferator-activated receptor [gamma] (PPAR[gamma]) plays an important role in adipose tissue formation by activating genes implicated in adipogenesis. PPAR[gamma] heterodimerizes with retinoid X receptor [alpha] (RXR[alpha]), in the presence of ligand, on PPAR response elements (PPREs) in the promoter of target genes involved in adipocyte differentiation. General receptor for phosphoinositides 1 (GRP1) is a corepressor of thyroid hormone receptors (TRs), a nuclear receptor like PPAR[gamma]. GRP1 decreases TRs' transcriptional activity by lowering dimerisation on DNA. Since PPARs and TRs have important structural similarities and that GRP1 interacts with PPARs in vitro, we hypothesized that GRP1 could be a coregulator of PPARs and, thus be implicated in adipogenesis. To better understand GRP1's effect on PPAR[gamma]2, transcriptional activity assays have been done and show that increasing concentrations of GRP1 decrease the transcriptional activity of PPAR[gamma]2. We also studied GRP1 expression by Western blots of total protein extracts from 3T3-L1 cells at different times during differentiation: GRP1 is present in 3T3-L1 preadipocytes and its expression decreases during adipogenesis. According to those results, GRP1 may be a PPAR[gamma] corepressor. After those observations, GRP1 effects on adipogenesis were studied by modulating its expression with lentiviral particles. Interestingly, GRP1 knock-down before inducing 3T3-L1 differentiation, almost abrogates adipogenesis and adipocytes markers, PPAR[gamma] and aP2, while its overexpression increases lipid storage without affecting PPAR[gamma] expression. On the opposite, GRP1 modulation after differentiation induction shows that expression knock-down slightly promotes adipogenesis by increasing PPAR[gamma], aP2 and lipid accumulation and that overexpression weakly decreases lipid storage. Our results suggest that GRP1 implication during adipogenesis occurs at two distinct and precise moments. It seems to be a key factor in the early stages of adipocyte differentiation and to be implicated as a PPAR[gamma] transcriptional activity modulator as a corepressor. Future experiments will help detail modulation of protein expression and underlying mechanisms to better understand the role of GRP1 in adipogenesis and, eventually, comorbidities linked to obesity like cardiovascular diseases and type 2 diabetes mellitus.

This thesis focuses on a clientele who currently lives with both a lower life expectancy and a lower quality of life due to obesity. The goal of this thesis is to identify and validate effective interventions for people living in a family environment with intellectual disabilities or treated with antipsychotic medication. Methods. Covering a period of five years, this research includes two studies, each lasting two years, evaluating two interventions. The first is a control-group study involving 82 participants. It assesses the effectiveness of interventions aimed at patient self-control and identifies lifestyle factors related to obesity in this population. The second study includes 7 families (comprised of 36 individuals) and 30 public health care professionals. It assesses the effectiveness of interventions, this time targeting the offer of food by the cooks and the support of public health care professionals. Measures : Body mass index (BMI), waist circumference (WC), antipsychotic medication use, family, lifestyle factors (physical activity, consumption of fruits and vegetables, smoking, duration of sleep), survey of food offer and physiological parameters (blood pressure, fasting glucose and lipid). Results. The WC is a more sensitive measure than BMI to detect obesity, particularly in women, who have a higher incidence of abdominal obesity. The family is a determining variable of the variation in the incidence of obesity. The practice of physical activity and the daily consumption of vegetables (excluding potatoes) are associated with less obesity. Interventions aimed at self-control are ineffective with this population. However, interventions aimed at the cooks and the health care professionals are significantly effective in reducing BMI as well as WC and in increasing the frequency of physical activity and consumption of fruits and vegetables, while improving the quality of the food offered. These improvements are maintained after two years. Conclusion. It appears that interventions specifically targeting the cook and involving the health care professionals are an efficient way to help this clientele.This thesis also highlights the usefulness for health care professionals to change from an intervention model of being the"expert", previously used primarily with an institutionalized clientele, to a model of"non-expert" focusing on collaboration, best suited for interventions on lifestyle factors in family environments.

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

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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

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